LARP7's measured readout is P-TEFb release and Pol II CTD Ser2 phosphorylation, not a histone mark - and the one compound shown to act through it disrupts the particle rather than the protein
also called LARP7 epigenetic readout · q181 LARP7
LARP7 clamps the 3' end of the 7SK RNA and keeps the transcription accelerator parked. When a drug knocks LARP7 off, the accelerator is released and starts marking polymerase for productive elongation - a change measured on the polymerase, not on the histones.
The same thing, for a scientist
gene-larp7 is one of the eight entries in this beat's sampling-free real-gap floor: no epigenetics field, no mark named, no chromatin concept. The literature that exists gives a clear readout and it is not a histone mark. MEPCE and LARP7 act cooperatively to stabilise 7SK and maintain the integrity of the 7SK snRNP, with MEPCE promoting the LARP7-7SK interaction. Functionally, gliotoxin disrupts 7SK snRNP by targeting LARP7, releasing active P-TEFb, which phosphorylates the RNA Pol II C-terminal domain and induces transcription - a measurement on the polymerase CTD, not on chromatin. The correct annotation is therefore a recorded CTD-level readout plus a bounded absence on the chromatin side, and NOT a category statement: the sibling entry mechanism-q181-7sk-occupies-enhancers-and-recruits-baf-so-the-brake-has-a-chromatin-address establishes that the particle LARP7 holds together has a genome-wide enhancer address, so a chromatin measurement for LARP7 exists to be made.
The two published handles on LARP7
Structural role. LARP7 binds the 3'-poly(U) of 7SK. MEPCE caps 7SK before its sequestration into the snRNP, and once LARP7 is bound MEPCE loses capping activity, probably because LARP7 occludes its catalytic centre; MEPCE then acts capping-independently to promote the LARP7-7SK interaction. The two act cooperatively to stabilise 7SK and maintain the integrity of the particle 1.
Functional role, with a chemical probe. In a screen of fungal metabolites for HIV latency-reversal agents, gliotoxin was found to reduce 7SK RNA, and to do so by directly targeting LARP7: it disrupts 7SK snRNP, releases active P-TEFb, and that P-TEFb phosphorylates the Pol II CTD 2.
The readout in both is the particle and the polymerase. Neither paper reports a histone modification.
The annotation this entry proposes, in the three-state form
| state | value |
|---|---|
| RECORDED | P-TEFb release from 7SK, read out as RNA Pol II CTD phosphorylation 2; cooperative stabilisation of 7SK with MEPCE 1 |
| BOUNDED ABSENCE | no histone mark, chromatin occupancy or accessibility measurement for LARP7 in any system, and none in any KMT2A-rearranged cell |
| NOT APPLICABLE | rejected -- the particle has an enhancer address and a nucleosome-level mechanism |
This is the shape the beat recommends for the dimension generally: a positive readout in the vocabulary the protein actually has, a named absence in the vocabulary it does not, and an explicit refusal of the category escape with the reason attached.
Relevance to this project, stated narrowly
LARP7 is named in 22 node files of this corpus without an entry-level epigenetics record. Its relevance to KMT2A::AFF1 is indirect and this entry does not overstate it: the index fusion's 3' partner AFF1 delivers P-TEFb to paused polymerase, and LARP7 governs how much P-TEFb is available to be delivered. This corpus already holds mechanism-kmt2a-aff1-cannot-be-sequestered-in-the-7sk-snrnp and mechanism-ptefb-extraction-from-the-7sk-reservoir, so the mechanism is written; what is new here is only the per-protein readout and the reason a chromatin measurement is owed rather than inapplicable.
Nothing in this entry is a KMT2A experiment. Gliotoxin's effect on LARP7 was measured in CD4 T cells and HeLa in an HIV-latency context.
| epigenetic readout | RNA Pol II C-terminal domain phosphorylation following P-TEFb release from 7SK (PMID 32851167); structural stabilisation of the 7SK scaffold cooperatively with MEPCE (PMID 19906723). Not a histone mark - LARP7 has no described histone or nucleosome substrate. |
|---|---|
| epigenetic bounded absence | No histone-mark, chromatin-occupancy or accessibility measurement for LARP7 in any system was found. None in any KMT2A-rearranged cell. |
| epigenetics not applicable | false |
| not applicable rejected because | The 7SK particle LARP7 stabilises occupies enhancers genome-wide and repositions nucleosomes via BAF (PMID 26878240), so a chromatin measurement for LARP7 exists to be made. |
| uniprot | Q4G0J3 |
| shown for fusion | NO - nobody has looked in any KMT2A fusion. The functional data are HIV latency in CD4 T cells and HeLa biochemistry. |
marks named
[]
chemical probe
{
"compound": "gliotoxin",
"target": "LARP7",
"effect": "disrupts 7SK snRNP, releases P-TEFb",
"system": "CD4 T cells, ex vivo primary cells",
"selectivity_caveat": "reactive epipolythiodioxopiperazine; selectivity rests on one report"
}measurements
[
{
"quantity": "node files naming LARP7 with no entry-level epigenetics record",
"value": 22,
"units": "node files",
"subject": "word-boundary naming count for LARP7 across the corpus, against gene-larp7 carrying no epigenetics field",
"universe": "3,032 node files at commit ac2aeab, via scripts/beat-inventory.py 2026-09-24",
"null": null,
"note": "the protein is discussed 22 times and annotated zero times on this dimension"
}
]- Releasing P-TEFb by disrupting the 7SK brake is the opposite of what a KMT2A-rearranged leukaemia needs: the fusion's pathology is excess productive elongation at HOXA and MEIS1. Any compound acting like gliotoxin would be expected to worsen, not help, and LARP7 is therefore a liability to avoid hitting rather than a target - including as an off-target of something else.
- Conversely, if a menin or DOT1L inhibitor reduces elongation at fusion targets, a cell could compensate by releasing P-TEFb from the 7SK pool, and LARP7 loss would be a plausible resistance mechanism nobody has looked for. Resistance screens in this disease have not reported LARP7, but they were not powered for it and the reserve pool is large.
- Gliotoxin is immunosuppressive and is an Aspergillus virulence factor. Any interest in it as a probe in a paediatric leukaemia context, where invasive aspergillosis is a real cause of death, needs saying out loud.
- Does LARP7 occupy chromatin in its own right, or only through 7SK? No LARP7 ChIP or CUT&RUN in any system was found.
- Is 7SK abundance or LARP7 level different in KMT2A-rearranged blasts than in normal progenitors? The corpus's noncoding-rn7sk entry notes nobody has counted 7SK copies per nucleus in a KMT2A-rearranged blast, and LARP7 sets 7SK stability, so the two questions are one experiment.
- Has any menin-inhibitor or DOT1L-inhibitor study measured 7SK or LARP7? If P-TEFb availability buffers the elongation defect these drugs induce, LARP7 is an obvious resistance node and no search in this beat covered it.
- Is gliotoxin's LARP7 effect selective enough to be a usable probe, or is it thiol reactivity? No selectivity literature was searched.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
MEPCE caps 7SK as a LARP7-free enzyme, probably co-transcriptionally and before sequestration into the snRNP; on interacting with LARP7 within the particle MEPCE loses capping activity, probably through occlusion of its catalytic centre by LARP7; MEPCE then displays a capping-independent function promoting the LARP7-7SK interaction, and MEPCE and LARP7 act cooperatively to stabilise 7SK and maintain the integrity of 7SK snRNP.
A capping-independent function of MePCE in stabilizing 7SK snRNA and facilitating the assembly of 7SK snRNP · Xue Y, Yang Z, Chen R, Zhou Q · Nucleic Acids Research 38(2):360-9 2009What this evidence cannot show
Abstract-level read; the full text was not retrieved. HeLa cells only. The paper hedges twice in its own abstract ('probably in a co-transcriptional manner', 'probably due to the occlusion'), and both hedges are carried through into the claim above rather than removed. expected_absent_terms names histone and nucleosome because the point of citing this paper here is that its readout is RNA-level, so their absence is part of the claim.
Evidence that argues against this (1)
- This is a 2009 biochemistry paper in one cell line and the field has moved: cryo-EM structures of the 7SK snRNP published since could revise the occlusion model, and no attempt was made in this beat to find them. A structural paper showing MEPCE's catalytic centre is not occluded by LARP7 would leave the cooperative-stabilisation conclusion intact but remove its proposed mechanism, which this entry states as though settled.
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Gliotoxin, identified in a screen of fungal secondary metabolites, directly disrupts the 7SK snRNP by targeting LARP7, releasing active P-TEFb which phosphorylates the RNA polymerase II C-terminal domain and induces transcription; RNA sequencing showed 7SK RNA significantly reduced on gliotoxin treatment of CD4 T cells.
Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency · Stoszko M, Al-Hatmi AMS, Skriba A, Roling M, Ne E, Crespo R, et al., Mahmoudi T · Science Advances 6(33):eaba6617 2020What this evidence cannot show
The system is HIV latency in CD4 T cells and ex vivo primary cells, not leukaemia and not any KMT2A-rearranged line. Gliotoxin is a promiscuous fungal toxin with well-documented immunosuppressive and thiol-reactive activity, so 'directly targeting LARP7' is a strong claim for a compound of this class and rests on this one report. The claim is cited here for the READOUT it establishes - CTD phosphorylation, not a histone mark - which does not depend on gliotoxin's selectivity.
Evidence that argues against this (2)
- No published disagreement with the LARP7-gliotoxin mechanism was located. The searches run were PubMed 'LARP7 7SK snRNP P-TEFb transcription' (26 records, titles of the top 10 checked) and 'LARP7 MEPCE 7SK snRNP P-TEFb stability core components' (0 records). That is a thin search and the absence should be read as unchecked rather than as a clean field - in particular no search was run for gliotoxin off-target or selectivity literature, which for a reactive epipolythiodioxopiperazine is where a contradiction would most likely be.
- The claim that LARP7's readout is CTD phosphorylation 'and not a histone mark' is an argument from what two papers happened to measure. Neither paper set out to test histone marks, so their silence is not evidence of absence - it is exactly the missing-value-scored-as-a-negative-value error. This entry records it as a bounded absence for that reason, but the summary's framing still leans on the two papers' choice of assay.
supplies the epigenetics record gene-larp7 lacks: CTD-level readout, chromatin measurement owed
the rejection of NOT APPLICABLE for LARP7 rests on the particle's enhancer address
gliotoxin-LARP7 is a chemical instance of extraction from the reservoir, in an HIV-latency system
MEPCE and LARP7 act cooperatively to stabilise 7SK; same source, two subunits