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Source ontology files for the Gene Ontology
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"histone demethylase activity" revisions/additions/obsoletions #21089

Closed sjm41 closed 2 years ago

sjm41 commented 3 years ago

I've just been reviewing the branch shown below (with current EC/RHEA xrefs):

histone demethylase activity
|__histone demethylase activity (H3-R2 specific)
|__histone demethylase activity (H4-R3 specific)
|__histone demethylase activity (H3-K4 specific)
|   |__histone demethylase activity (H3-monomethyl-K4 specific)
|   |__histone demethylase activity (H3-dimethyl-K4 specific)
|   |__histone demethylase activity (H3-trimethyl-K4 specific) (EC:1.14.11.67)
|__histone demethylase activity (H3-K9 specific) (EC:1.14.11.65, EC:1.14.11.66)
|__histone demethylase activity (H4-K20 specific)
|__histone demethylase activity (H3-K27 specific) (EC:1.14.11.68)
|__histone demethylase activity (H3-K36 specific) (EC:1.14.11.27, RHEA:42032)

Looks like several improvements should be made to:

Some specific suggestions below (indicated by '=>') - note I've omitted the synonyms/Reactome xrefs for brevity:

[Term] id: GO:0032452 name: histone demethylase activity namespace: molecular_function def: "Catalysis of the removal of a methyl group from a histone." [GOC:mah] is_a: GO:0140457 ! protein demethylase activity

[Term] id: GO:0033746 name: histone demethylase activity (H3-R2 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from arginine at position 2 of the histone H3 protein." [GOC:mah] is_a: GO:0032452 ! histone demethylase activity => (can't find EC/RHEA for this)

[Term] id: GO:0033749 name: histone demethylase activity (H4-R3 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from arginine at position 3 of the histone H4 protein." [GOC:mah] is_a: GO:0032452 ! histone demethylase activity => (can't find EC/RHEA for this)

[Term] id: GO:0032453 name: histone demethylase activity (H3-K4 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from lysine at position 4 of the histone H3 protein." [GOC:mah] is_a: GO:0032452 ! histone demethylase activity => add additional child term for RHEA:60212 (2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl4-[histone H3] + O2 = CO2 + formaldehyde + N6,N6-dimethyl-L-lysyl4-[histone H3] + succinate)

[Term] id: GO:0034649 name: histone demethylase activity (H3-monomethyl-K4 specific) namespace: molecular_function def: "Catalysis of the reaction: histone H3 N6-methyl-L-lysine (position 4) + O2 + FAD + H2O = histone H3 L-lysine (position 4) + H2O2 + formaldehyde + FADH2. This reaction is the removal of a methyl group from monomethylated lysine at position 4 of the histone H3 protein." [GOC:mah, PMID:16223729] is_a: GO:0016705 ! oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen is_a: GO:0032453 ! histone demethylase activity (H3-K4 specific) => add RHEA:60220 (2-oxoglutarate + N6-methyl-L-lysyl4-[histone H3] + O2 = CO2 + formaldehyde + L-lysyl4-[histone H3] + succinate)

[Term] id: GO:0034648 name: histone demethylase activity (H3-dimethyl-K4 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from dimethylated lysine at position 4 of the histone H3 protein." [GOC:mah, PMID:17550896] is_a: GO:0032453 ! histone demethylase activity (H3-K4 specific)

[Term] id: GO:0034647 name: histone demethylase activity (H3-trimethyl-K4 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from trimethylated lysine at position 4 of the histone H3 protein." [GOC:mah, PMID:17550896] xref: EC:1.14.11.67 is_a: GO:0032453 ! histone demethylase activity (H3-K4 specific) => add RHEA:60208 (3 2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl4-[histone H3] + 3 O2 = 3 CO2 + 3 formaldehyde + L-lysyl4-[histone H3] + 3 succinate)

[Term] id: GO:0032454 name: histone demethylase activity (H3-K9 specific) namespace: molecular_function def: "Catalysis of the reaction: histone H3 N6-methyl-L-lysine (position 9) + alpha-ketoglutarate + O2 = succinate + CO2 + formaldehyde + lysine. This reaction is the removal of a methyl group from lysine at position 9 of the histone H3 protein." [PMID:16362057] xref: EC:1.14.11.65 xref: EC:1.14.11.66 is_a: GO:0032452 ! histone demethylase activity => make 5 child terms and move EC numbers to first two: 1) RHEA:60188 2 2-oxoglutarate + N6,N6-dimethyl-L-lysyl9-[histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + L-lysyl9-[histone H3] + 2 succinate (EC:1.14.11.65) 2) RHEA:60200 2 2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl9-[histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N6-methyl-L-lysyl9-[histone H3] + 2 succinate (EC:1.14.11.66) 3) RHEA:60192 2-oxoglutarate + N6,N6-dimethyl-L-lysyl9-[histone H3] + O2 = CO2 + formaldehyde + N6-methyl-L-lysyl9-[histone H3] + succinate
4) RHEA:60196 2-oxoglutarate + N6-methyl-L-lysyl9-[histone H3] + O2 = CO2 + formaldehyde + L-lysyl9-[histone H3] + succinate 5) RHEA:60204 2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl9-[histone H3] + O2 = CO2 + formaldehyde + N6,N6-dimethyl-L-lysyl9-[histone H3] + succinate

[Term] id: GO:0035575 name: histone demethylase activity (H4-K20 specific) namespace: molecular_function def: "Catalysis of the reaction: histone H4 N6-methyl-L-lysine (position 20) + 2-oxoglutarate + O2 = histone H4 L-lysine (position 20) + succinate + formaldehyde + CO2. This reaction is the removal of a methyl group from lysine at position 20 of the histone H4 protein." [PMID:20622853] is_a: GO:0032452 ! histone demethylase activity => (can't find EC/RHEA for this)

[Term] id: GO:0071558 name: histone demethylase activity (H3-K27 specific) namespace: molecular_function def: "Catalysis of the removal of a methyl group from lysine at position 27 of the histone H3 protein." [GOC:sp, PMID:20622853] xref: EC:1.14.11.68 is_a: GO:0032452 ! histone demethylase activity => make 3 child terms corresponding to these RHEAs and move EC xref to first one

  1. RHEA:60224 2 2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl27-[histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N6-methyl-L-lysyl27-[histone H3] + 2 succinate (EC:1.14.11.68)
  2. RHEA:60228 2-oxoglutarate + N6,N6,N6-trimethyl-L-lysyl27-[histone H3] + O2 = CO2 + formaldehyde + N6,N6-dimethyl-L-lysyl27-[histone H3] + succinate
  3. RHEA:60232 2-oxoglutarate + N6,N6-dimethyl-L-lysyl27-[histone H3] + O2 = CO2 + formaldehyde + N6-methyl-L-lysyl27-[histone H3] + succinate

[Term] id: GO:0051864 name: histone demethylase activity (H3-K36 specific) namespace: molecular_function def: "Catalysis of the reaction: histone H3 N6-methyl-L-lysine (position 36) + alpha-ketoglutarate + O2 = succinate + CO2 + formaldehyde + lysine. This reaction is the removal of a methyl group from lysine at position 36 of the histone H3 protein." [PMID:16362057] xref: EC:1.14.11.27 xref: MetaCyc:RXN-8660 xref: MetaCyc:RXN-8661 xref: RHEA:42032 is_a: GO:0016706 ! 2-oxoglutarate-dependent dioxygenase activity is_a: GO:0032452 ! histone demethylase activity

sjm41 commented 3 years ago

Also note that "protein demethylase activity (GO:0140457)" has "histone demethylase activity (GO:0032452)" as its single child term, and all annotations appear to be on the latter. So maybe they should be merged?

sjm41 commented 3 years ago

Hi @hdrabkin Would you have any thoughts on this one?

pgaudet commented 3 years ago

I'll take this as part of the transcription project.

pgaudet commented 3 years ago
pgaudet commented 3 years ago

Also note that "protein demethylase activity (GO:0140457)" has "histone demethylase activity (GO:0032452)" as its single child term, and all annotations appear to be on the latter. So maybe they should be merged?

I will not do that, as there are other substrates such as the ER receptor (see PMID:24498420 cited in GO:0140457).

The histone code has an important biological significance, for now we have decided to capture it in GO.

pgaudet commented 3 years ago
pgaudet commented 3 years ago

Hi @sjm41 I made a number of changes, except for the specific tri/di/mono methyl reactions, since in Rhea at least some of them are represented as multistep reactions: for eg RHEA:60208 trimethyl-K4 -> unmethylated-K4 states: multi step reaction: (1) tri -> dimethy; (2) di -> monomethyl ; -> (3) mono -> unmethylated

From looking quickly it seems that indeed the same enzyme catalyzes the step-wise demethylation, so I may merge |histone demethylase activity (H3-K4 specific) | |histone demethylase activity (H3-monomethyl-K4 specific) | |histone demethylase activity (H3-dimethyl-K4 specific) | |histone demethylase activity (H3-trimethyl-K4 specific) (EC:1.14.11.67) which would anyway correspond to EC:1.14.11.67, as this also states that the enzyme can act on tri, di, and momomethylated lysines.

I just want to check the annotations to make sure there is no enzyme specific for any one of the modifications.

Let me know if you are aware that these take place as individual reactions.

@colinlog may be able to help on this.

Thanks, Pascale

sjm41 commented 3 years ago

Thanks for working on this. You've made all the key changes - I'd missed that the tri/di methylations were multistep reactions (which of course makes sense). I'd just noticed the apparent inconsistency that some GO terms had children for these steps and some didn't. Merging the histone demethylase activity (H3-K4 specific) children into the parent would also fix that issue. I don't know of enzymes specific for each modification myself, but the existence of EC:1.14.11.65 and EC:1.14.11.66 suggests there might be?

ValWood commented 3 years ago

Hi,

Sorry to be late commenting here. I had a distant memory that not all histone demethylases are 2-oxoglutarate-dependent dioxygenase dependent, (i.e these is a difference between SWIRM and Lsd) but I could not easily find the papers describing the different mechanisms, so it fell off my radar. Anway Wikipedia seems to confirm this: https://en.wikipedia.org/wiki/Demethylase

Cofactors include: alpha-keto glutarate (JmjC-domain containing demethylases), CoREST (LSD), FAD, Fe (II) or NOG (N-oxalylglycine).[4] Domains include:

SWIRM1 (Swi3, Rsc, and Moira domain): Proposed anchor site for histone molecules; found in several chromatin modifying complexes; facilitates demethylase protein and co-factor CoREST (nucleosomal substrate binding)[5] Jumonji (N/C terminal domains): Binding domain of key cofactors such as alpha-keto glutarate; connected by a beta-hairpin/mixed domain[4][6] PHD-finger: hydrophobic cage of residues that acts to bind methylated peptides; plays key role in recognition and selectivity for methylated histone residues[4] Zinc-finger: DNA binding domain[4] Amine oxidase domain: catalytic active site of LSD proteins; larger than related proteins to help fit size of the histone tail [4]

sjm41 commented 3 years ago

Thanks Val!

So that wikipedia page says: Defined by their mechanisms, two main classes of histone demethylases exist: (i) a flavin adenine dinucleotide (FAD)-dependent amine oxidase, and (ii) an Fe(II) and α-ketoglutarate-dependent hydroxylase.

Far as I can tell from that page and looking up domains of the human proteins, the FAD-dependent mechanism is only used by:

KDM1 family

All other family members are α-ketoglutarate-dependent:

KDM2 family

KDM3 family

KDM4 family

KDM5 family

KDM6 family

So...it seems there's not a clean distinction between the different dependencies and the substrate (as specified in the GO terms), so it's going to be tricky adding accurate oxidoreductase parents....

Here's how things look if I map the info from the wikipedia page onto the tree:

histone demethylase activity
|__histone demethylase activity (H3-R2 specific)
|__histone demethylase activity (H4-R3 specific)
|__histone demethylase activity (H3-K4 specific)
|   |__histone demethylase activity (H3-monomethyl-K4 specific) = KDM1 (FAD-dependent amine oxidase)
|   |__histone demethylase activity (H3-dimethyl-K4 specific) = KDM1 (FAD-dependent amine oxidase), KDM5 (α-ketoglutarate-dependent hydroxylase)
|   |__histone demethylase activity (H3-trimethyl-K4 specific) = KDM2 & KDM5 (α-ketoglutarate-dependent hydroxylase)
|__histone demethylase activity (H3-K9 specific) = KDM1 (FAD-dependent amine oxidase), KDM3 & KDM4 (α-ketoglutarate-dependent hydroxylase)
|__histone demethylase activity (H4-K20 specific)
|__histone demethylase activity (H3-K27 specific) = KDM6 (α-ketoglutarate-dependent hydroxylase)
|__histone demethylase activity (H3-K36 specific) = KDM2 & KDM4 (α-ketoglutarate-dependent hydroxylase)

Looking at QuickGO just now, only these two histone demethylase terms have an oxidoreducatase parent:

histone demethylase activity (H3-monomethyl-K4 specific) (GO:0034649)

histone demethylase activity (H3-K36 specific) (GO:0051864)

I'm not sure how to best proceed here....probably need to do more reading to verify the wikipedia details and also find out about the mechanism of the GO terms not mentioned on that page.

sjm41 commented 3 years ago

FYI - I edited my previous comment to include the mappings to the existing GO terms.

sjm41 commented 3 years ago

Couple of useful reviews:

From PMID: 22473470, Figure 1: "The two different reaction mechanisms used by Lys-specific demethylase 1 (LSD1) and LSD2 [i.e. KDM1 family] (a) and the Jumonji C (JMJC) family (b) of demethylases are depicted. a | The flavin adenine dinucleotide (FAD)-dependent amine oxidation reaction is used by LSD1 and LSD2 to demethylate mono- and dimethylated substrates. b | The JMJC family uses a dioxygenase reaction that is dependent on Fe(II) and α-ketoglutarate for demethylating mono-, di- and trimethylated residues."

So, it seems both types use an oxidation mechanism to catalyse the demethylation, so I think all the GO terms should have an oxidoreductase parent (at some level). If we're convinced that some GO terms apply ONLY to JMJC family Demethylases (KDM2-8), then those GO terms could have a "2-oxoglutarate-dependent dioxygenase activity" parent, whereas GO terms that apply ONLY to LSD family demethylases (KDM1) or apply to both types, could have a higher-level oxidoreductase parent (maybe top-level "oxidoreductase activity").

ValWood commented 3 years ago

There was a comment that thee specificity will be deleted here, so I opened this ticket for PomBase: https://github.com/pombase/curation/issues/3042 however, the comment

"As far as I can tell, there is no demethlyase with specificity for either tri, di- or mono methlyated histone lysine, so I will merge" is gone. So not sure if I need to priorities this...?

pgaudet commented 3 years ago

"As far as I can tell, there is no demethlyase with specificity for either tri, di- or mono methlyated histone lysine, so I will merge"

I deleted this because as @sjm41 pointed out, there is at least one enzyme that doesn't act on the tri-methylated histone (LSD1) and LSD2 [i.e. KDM1 family)

pgaudet commented 3 years ago

I am not sure how to handle this one. We are missing at least some substrates (for example monomethylated and dimethylated lysine 20 in histone H4 are mentioned in PMID:33318631), and the specificity of the enzymes do not align with the current MF structure, for example in the same paper, LSD1 has substrates H3K4me1/2 and H3K9me1/2, as well as H4K20me1/2.

We dont typically capture mechanisms, so I would prefer not to create FAD-dependent and α-ketoglutarate-dependent versions of the different enzymes.

Also about the H3-K4: I dont know why we have the specific mono, di, tri methyl versions, and not for others, like K20.

pgaudet commented 3 years ago

Maybe we are following EC:

pgaudet commented 3 years ago

Well, no, since they only have a 2 H3K4 reactions and we have 3; and they have 2 H3K9 reactions and we have one.

I'll see if we can align on RHEA.

ValWood commented 3 years ago

Also about the H3-K4: I dont know why we have the specific mono, di, tri methyl versions, and not for others, like K20.

At PomBase we have only requested terms where we have data, and we have no data for K20 specific demethylases. The demethylases have been identified relatively recently (i.e last decade) and it is possible that this is not yet known for all methylated histone residues.

deustp01 commented 3 years ago

We dont typically capture mechanisms,

Really? To the extent that MF distinctions follow EC, they do capture mechanisms, and anyway this kind of mechanistic distinction is important biologically - that difference in co-factor almost certsinly points to a difference in protein family / subfamily and to different physiological conditions in which the r4eaction is happening. @ukemi

pgaudet commented 3 years ago

This is right. I should probably have written, we dont systematically capture mechanisms.

deustp01 commented 3 years ago

... and I should have phrased my comment as a request for an exception. I suspect that this is a general (and annoying) problem: It's very hard to find uniform algorithms to define granularity boundaries that also reliably capture biologically important distinctions - even the best general formulas I know need individual tweaking.

pgaudet commented 3 years ago

Hello,

I checked EC and RHEA, and they are aligned for all the activities, so I propose we do the same. This involves the following changes:

H3-K36

See https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876457093 and https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876502770

~GO:0051864 histone demethylase activity (H3-K36 specific)
Mapped to EC:1.14.11.27 [Histone H3]-dimethyl-L-lysine-36 demethylase.
Mapped to RHEA:42032 dimethylated to unmethylated (multistep reaction)
EXP annotations: 28 Actions:

~NTR: histone H3-trimethyl-L-lysine-36 demethylase activity

H3-K27

See https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876419565

~GO:0071558 histone demethylase activity (H3-K27 specific)

H3-K9

See https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876941728 and https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876942969

~GO:0032454 histone H3-K9 demethylase activity
Mapped to EC:1.14.11.65 [Histone H3]-dimethyl-L-lysine-9 demethylase.
Mapped to RHEA:60188 dimethylated to unmethylated (multistep reaction) (Missing from GO) EXP annotations:43
Obsolete and replace by 2 terms:~

~NTR: histone H3-dimethyl-L-lysine-9 demethylase activity

~NTR: histone H3-trimethyl-L-lysine-9 demethylase activity

H3K4

See https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876543726
~GO:0034647 histone demethylase activity (H3-trimethyl-K4 specific) -> 13 EXP

~NTR: histone H3-dimethyl-L-lysine-4 FAD-dependent demethylase activity

~GO:0032453 histone demethylase activity (H3-K4 specific) -> 20 EXP

Others

No EC, No RHEA correspond to the following reactions:

Parent class

histone demethylase activity 15 EXP -> add DO NOT ANNOTATE

@sjm41 @deustp01 Is that OK for you?

pgaudet commented 3 years ago
ValWood commented 3 years ago

Are you sure? I have 2 predicted histone demethylases for which I don't know the specificity (jmj2 and 4)

ValWood commented 3 years ago

Also,I have been meaning to ask, should the word "specific" be removed from these terms?

histone demethylase activity (H3-trimethyl-K4 specific) specific could be confused to mean this is the only residue demethylated?

pgaudet commented 3 years ago

Really? jmj2 is annotated to histone demethylase activity (H3-trimethyl-K4 specific) Source: PomBase histone demethylase activity (H3-dimethyl-K4 specific) Source: PomBase histone demethylase activity (H3-K36 specific) Source: PomBase histone demethylase activity (H3-K4 specific) Source: PomBase

not sure about the Pfam evidence for http://pfam.xfam.org/family/PF02373 "The JmjC domain belongs to the Cupin superfamily [3]. JmjC-domain proteins may be protein hydroxylases that catalyse a novel histone modification [4]."

ValWood commented 3 years ago

Sorry I mean jmj1 & 4

pgaudet commented 3 years ago

GO:0071558 histone demethylase activity (H3-K27 specific)

pgaudet commented 3 years ago

jmj1 & 4

Are you sure your mapping from PF02373 is correct?

pgaudet commented 3 years ago

GO:0051864 histone demethylase activity (H3-K36 specific)

GO:0051864 histone demethylase activity (H3-K36 specific)

It may be possible to annotate to a more specific term (although the correspondence to the ECs is less clear than for other histone demethylases): Annotations: https://docs.google.com/spreadsheets/d/1GbU-e8i95rsA0qaMNZmhp7l3-noUYHL9oeFVbgsJkHE/edit#gid=0

pgaudet commented 3 years ago

+[Term] +id: GO:0140680 +name: histone H3-di/mono-methyl-lysine-36 demethylase activity +namespace: molecular_function +def: "Catalysis of the removal of a methyl group from a di- or a mono-methyl-lysine residue at position 36 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:20531378] +synonym: "histone H3K36me demethylase activity" RELATED [] +synonym: "histone H3K36me2 demethylase activity" BROAD [] +is_a: GO:0051864 ! histone H3-methyl-lysine-36 demethylase activity +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI +created_by: pg +creation_date: 2021-07-08T14:12:22Z + +[Term] +id: GO:0140681 +name: histone H3-tri/dimethyl-lysine-36 demethylase activity +namespace: molecular_function +def: "Catalysis of the removal of a methyl group from a tri-methyl-lysine or a di-methyl-lysine residue at position 36 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:21914792] +synonym: "histone H3K36me2 demethylase activity" BROAD [] +synonym: "histone H3K36me3 demethylase activity" RELATED [] +xref: EC:1.14.11.69 {source="skos:exactMatch"} +xref: MetaCyc: RXN-8660 +xref: RHEA:60236 +is_a: GO:0051864 ! histone H3-methyl-lysine-36 demethylase activity +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI +created_by: pg +creation_date: 2021-07-08T14:12:31Z

pgaudet commented 3 years ago

GO:0032453 histone demethylase activity (H3-K4 specific)

GO:0034647 histone demethylase activity (H3-trimethyl-K4 specific) -> 13 EXP

NTR: histone H3-di/mono-methyl-lysine-4 FAD-dependent demethylase activity

GO:0032453 histone demethylase activity (H3-K4 specific)

-> 20 EXP

GO:0034649 histone demethylase activity (H3-monomethyl-K4 specific)

Obsolete -> 5 EXP

GO:0034648 histone demethylase activity (H3-dimethyl-K4 specific)

Obsolete -> 13 EXP

Replace as suggested in https://docs.google.com/spreadsheets/d/1Te65Plm-bTVVkJL0CDZT1Dhwf-HYfR1gCR8-QaPdx2o/edit#gid=0

Specific mono and di: https://docs.google.com/spreadsheets/d/1mlEpZji59zgeTQaxan0Ky6hE8B7rEjrrGRg9RpfcatE/edit#gid=0

pgaudet commented 3 years ago
pgaudet commented 3 years ago

[Term] id: GO:0140682 name: histone H3-di/mono-methyl-lysine-4 FAD-dependent demethylase activity def: "Catalysis of the removal of a methyl group from a di- or a mono-methyl-lysine residue at position 4 of the histone H3 protein. This is a flavin adenine dinucleotide (FAD)-dependent amine oxidation reaction." [PMID:22473470] xref: EC:1.14.99.66 xref: RHEA:60244 is_a: GO:0016705 ! oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen is_a: GO:0032453 ! histone demethylase activity (H3-K4 specific) property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI created_by: pg creation_date: 2021-07-08T15:45:22Z

ValWood commented 3 years ago

jmj1 & 4 Are you sure your mapping from PF02373 is correct?

Maybe it is too specific. I'm not sure these are histone demethylases?

Jmj4 appears to be a histone demethylase (human ortholog JMJD7) but jmj1, (human ortholog JMJD4) possibly not? I expected the jumonjo specificities to be different (analogous to the set family of methyltransferases see https://www.pombase.org/term/GO:0042054)

and currently we don't know the proteins that reverse all of the known histone methylation marks (or do we ? @colinlog ). I don't even know if they are all reversible....

pgaudet commented 3 years ago

and currently we don't know the proteins that reverse all of the known histone methylation marks (or do we ? @colinlog ). I don't even know if they are all reversible....

For sure. But other than K36 (see https://github.com/geneontology/go-ontology/issues/21089#issuecomment-876457093), the data I looked at in papers matched pretty well the EC/Rhea families. We can remove the do not annotate if needed.

ValWood commented 3 years ago

I would like to be able to annotate to "histone demethylase activity" for family members with no experimental data. If these are like set domain we can't assume that all members have the same specificity.

The methyltransferase specificities: Systematic ID | Gene name | Product description SPAC29B12.02c | set2 | histone lysine H3-K36 methyltransferase Set2 SPCC297.04c | set7 | histone lysine H3-K37 methyltransferase Set7 SPCC306.04c | set1 | histone lysine H3-K4 methyltransferase Set1 SPBC428.08c | clr4 | histone lysine H3-K9 methyltransferase Clr4 SPCC4B3.12 | set9 | histone lysine H4-K20 methyltransferase Set9 SPAC22E12.11c | set3 | histone lysine methyltransferase Set3 SPCC1739.05 | set5 | histone lysine methyltransferase Set5 (predicted) SPBP8B7.07c | set6 | histone lysine methyltransferase Set6 (predicted)

pgaudet commented 3 years ago

GO:0032454 histone H3-K9 demethylase activity

GO:0032454 histone H3-K9 demethylase activity: keep as grouping term, and add specific children

NTR: histone H3-di/monomethyl-lysine-9 demethylase activity

NTR: histone H3-tri/dimethyl-lysine-9 demethylase activity

EXP Annotations to GO:0032454 https://docs.google.com/spreadsheets/d/1x3WOUqg63QLg-Lz5CZFieDG32Yb3qP_GVVj2-2Pxlso/edit#gid=0

pgaudet commented 3 years ago

+[Term] +id: GO:0140683 +name: histone H3-di/monomethyl-lysine-9 demethylase activity +namespace: molecular_function +def: "Catalysis of the removal of a methyl group from a di or a monomethyl-lysine residue at position 9 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:16603238] +synonym: "histone H3-K9me2 demethylase activity" BROAD [] +synonym: "histone H3-K9me3 demethylase activity" RELATED [] +xref: EC:1.14.11.66 +xref: RHEA:60200 +is_a: GO:0016706 ! 2-oxoglutarate-dependent dioxygenase activity +is_a: GO:0032454 ! histone H3-methyl-lysine-9 demethylase activity +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI +created_by: pg +creation_date: 2021-07-09T06:03:06Z + +[Term] +id: GO:0140684 +name: histone H3-tri/dimethyl-lysine-9 demethylase activity +namespace: molecular_function +def: "Catalysis of the removal of a methyl group from a tri or a dimethyl-lysine residue at position 9 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:20208542, PMID:20531378] +synonym: "histone H3K9me demethylase activity" RELATED [] +synonym: "histone H3K9me2 demethylase activity" BROAD [] +xref: EC:1.14.11.65 +xref: RHEA:60188 +is_a: GO:0016706 ! 2-oxoglutarate-dependent dioxygenase activity +is_a: GO:0032454 ! histone H3-methyl-lysine-9 demethylase activity +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI +created_by: pg +creation_date: 2021-07-09T06:03:55Z

pgaudet commented 3 years ago

@ValWood I removed the DO NOT ANNOTATE from the parent class histone demethylase activity.

pgaudet commented 3 years ago

Dear all,

The proposal has been made to obsolete GO:0034649 histone demethylase activity (H3-monomethyl-K4 specific) and GO:0034648 histone demethylase activity (H3-dimethyl-K4 specific)

The reason for obsoletion is to align with RHEA and EC: these reactions are sub-reactions of both RHEA and EC. These terms have 5 and 13 EXP annotations, respectively. GO:0034648 is mapped to RHEA:60216, but this is part of RHEA:60208, which corresponds to GO:0034647.

Suggestions to move existing annotations are here: https://docs.google.com/spreadsheets/d/1mlEpZji59zgeTQaxan0Ky6hE8B7rEjrrGRg9RpfcatE/edit#gid=0 (note that this requires a GO term created yesterday).

We are opening a comment period for this proposed obsoletion. We’d like to proceed and obsolete this term on July 26, to leave time for groups to make corrections. Unless objections are received by July 26, 2021, we will assume that you agree to this change.

You may comment on the ticket: https://github.com/geneontology/go-ontology/issues/21089

Thanks, Pascale

pgaudet commented 3 years ago

NTR 'histone H3-di/monomethyl-lysine-9 FAD-dependent demethylase activity'

+[Term] +id: GO:0140685 +name: histone H3-di/monomethyl-lysine-9 FAD-dependent demethylase activity +namespace: molecular_function +def: "Catalysis of the removal of a methyl group from a di- or a monomethyl-lysine residue at position 9 of the histone H3 protein. This is a flavin adenine dinucleotide (FAD)-dependent amine oxidation reaction." [PMID:22473470] +synonym: "histone H3K9me demethylase activity" BROAD [] +synonym: "histone H3K9me2 demethylase activity" BROAD [] +is_a: GO:0032454 ! histone H3-methyl-lysine-9 demethylase activity +property_value: term_tracker_item https://github.com/geneontology/go-ontology/issues/21089 xsd:anyURI +created_by: pg +creation_date: 2021-07-09T07:18:00Z

sjm41 commented 3 years ago

Hi @pgaudet

Looks like the EC & Rhea xrefs and the synonyms need to be swapped on these two:

+id: GO:0140683 +name: histone H3-di/monomethyl-lysine-9 demethylase activity +def: "Catalysis of the removal of a methyl group from a di or a monomethyl-lysine residue at position 9 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:16603238] +synonym: "histone H3-K9me2 demethylase activity" BROAD [] +synonym: "histone H3-K9me3 demethylase activity" RELATED [] +xref: EC:1.14.11.66 +xref: RHEA:60200

+id: GO:0140684 +name: histone H3-tri/dimethyl-lysine-9 demethylase activity +def: "Catalysis of the removal of a methyl group from a tri or a dimethyl-lysine residue at position 9 of the histone H3 protein. This is a dioxygenase reaction that is dependent on Fe(II) and 2-oxoglutarate." [PMID:20208542, PMID:20531378] +synonym: "histone H3K9me demethylase activity" RELATED [] +synonym: "histone H3K9me2 demethylase activity" BROAD [] +xref: EC:1.14.11.65 +xref: RHEA:60188

pgaudet commented 3 years ago

Thanks for spotting this!

sjm41 commented 3 years ago

@pgaudet I was just about to mention that we also need a FAD-dependent H3-di/monomethyl-lysine-9 demethylase, but I notice you added this as GO:0140685 this morning - thanks! I think that needs the "is_a: GO:0016705 ! oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen" parent adding?

pgaudet commented 2 years ago

Annotation review ticket: https://github.com/geneontology/go-annotation/issues/3871

sjm41 commented 1 year ago

Just adding the final hierarchy we implemented here, for the record:

histone demethylase activity
|__histone H3-methyl-arginine-2 demethylase activity
|__histone H3-methyl-arginine-3 demethylase activity
|__histone H3-methyl-lysine-4 demethylase activity
|   |__histone H3-di/monomethyl-lysine-4 FAD-dependent demethylase activity (EC:1.14.99.66/RHEA:60244)
|   |__histone H3-tri/di/monomethyl-lysine-4 demethylase activity (EC:1.14.11.67/RHEA:60208)
|__histone H3-methyl-lysine-9 demethylase activity
|   |__histone H3-di/monomethyl-lysine-9 demethylase activity (EC:1.14.11.65/RHEA:60188)
|   |__histone H3-di/monomethyl-lysine-9 FAD-dependent demethylase activity
|   |__histone H3-tri/dimethyl-lysine-9 demethylase activity (EC:1.14.11.66/RHEA:60200)
|__histone H3-methyl-lysine-36 demethylase activity
|   |__histone H3-di/monomethyl-lysine-36 demethylase activity (EC:1.14.11.27/RHEA:42032)
|   |__histone H3-tri/dimethyl-lysine-36 demethylase activity (EC:1.14.11.69/RHEA:60236)
|__histone H3-tri/di-methyl-lysine-27 demethylase activity (EC:1.14.11.68/RHEA:60224)
|__histone H3-tri/dimethyl-lysine-56 demethylase activity
|__histone H4-methyl-lysine-20 demethylase activity
ValWood commented 1 year ago

Will the same heirarchy be added for example:

histone H3-tri/dimethyl-lysine-36methylase activity?

colinlog commented 1 year ago

@ValWood I believe most of the histone methylase activity terms are there and I guess it will be the same hierarchy, eccept that we are talking about different EC numbers and a different hierarchy of eactivities, aren't we?

Furthermore, how to express that one enzyme is only able to monomethylate but not di- or trimethylate a particular lysine?

In a GO-CAM the relation between the activities would be 'provides substrate for'. In protein to GO it is an extension with the same relation.

Example 1: the human H3K4 monomethylase MLL4 https://www.uniprot.org/uniprotkb/Q9UMN6/entry Example 2: the human H3K4me2/3 methylase MLL1 https://www.uniprot.org/uniprotkb/Q03164/entry

with a figure from PMID: 34440566 here ( https://pubmed.ncbi.nlm.nih.gov/34440566/#&gid=article-figures&pid=figure-2-uid-1 ) to explain the concept visually.

Note that in Uniprot only the monomethylation activity is displayed, also for MLL1 which is a H3K4 di- and trimethylase.

ValWood commented 1 year ago

No worries, I had a note to update set2 to histone H3-tri/dimethyl-lysine-36methylase activity and then I realize this was about demethylases. So I was just curious if there would be an. equivalent

histone H3-tri/dimethyl-lysine-36methylase activity. It was just a question, but it isn't a big deal. I'm sure it will exist eventually. I wondered if it was on @sjm41 s future radar.