ZC3H8 / Fliz1 - the last little-elongation-complex subunit without an entry, discovered in fetal liver haematopoietic progenitors, and a selective BioID2 bait that reaches KMT2A in K562

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• ZC3H8 is depleted in 91% of DepMap lines and its KMT2A-selectivity difference is POSITIVE. Any intervention aimed at it would be a broad-spectrum toxicity with the arm of interest among the less sensitive, which is the worst possible therapeutic shape.
• If ELL's pan-essentiality really is LEC rather than SEC, then targeting the ELL slot of the super elongation complex risks killing snRNA transcription in every cell in the body - and this entry strengthens the case that the LEC job is real by adding its fourth subunit, so it makes that risk more concrete rather than less.
• The fetal-liver origin story is exactly the kind of coincidence that hardens into a premise. It is a 2001 mouse expression pattern and nothing more, and if it is cited as support for a developmental model of KMT2A::AFF1 initiation without a functional experiment, this entry will have done harm.

1. Is ZC3H8 required for little elongation complex function, or only a member of it? The founding LEC paper assigns the initiation step to ICE1 and the elongation step to ELL and assigns ZC3H8 nothing. A ZC3H8 degron with a nascent snRNA readout would settle a question that has been open since 2013 and would tell this graph whether ELL's pan-essentiality can be attributed to a complex whose fourth subunit may be dispensable.
2. Does Fliz1/ZC3H8 have any haematopoietic function? Its founding observation is restricted foci of the E12 mouse fetal liver and Lin-/cKit+ progenitors - the compartment this project models as the KMT2A::AFF1 cell of origin - and in twenty-five years nobody has followed it up. A conditional knockout in fetal liver HSCs is the obvious experiment and none exists.
3. The only functional in-vivo study of a Zc3h8 orthologue reports NF-kB de-repression in zebrafish digestive organs, with no transcription-elongation phenotype. Are the LEC role and the NF-kB role the same activity seen from two directions, or is one of them an artefact of the system it was found in?
4. Are snRNA genes differentially transcribed in KMT2A-rearranged leukaemia? The LEC-SEC connection runs entirely through ELL, and this graph has argued that ELL's essentiality is about LEC rather than the fusion. Nobody has measured nascent snRNA output in a KMT2A-rearranged line, which is the direct test of whether the ELL slot is doing two jobs at once.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Khoroshkin et al. fused BioID2 to 50 human RNA-binding proteins in K562 cells and deposited the curated pair list as IMEx IM-30059; ZC3H8 is one of the 50 baits and KMT2A is among its recovered preys.

   Systematic identification of post-transcriptional regulatory modules. · Khoroshkin M, Buyan A, Dodel M, Navickas A, Yu J, Trejo F, et al. · Nat Commun 2024
   PMID 39251607DOI
   ▸What this evidence cannot show

   Abstract read; full text not read. The authors state that RBP over-expression, BioID2 fusion and the use of a single isoform per protein may bias the data. K562 carries BCR::ABL1 and no KMT2A rearrangement.

   ▸Evidence that argues against this (1)

   • The bait panel is 50 RNA-binding proteins, so a prey resident in the RNA-processing compartment is recovered widely for a compartment reason. KMT2A is recovered by 25 of the 50 and this graph has already traced that breadth largely to its size. source 2026
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   IntAct serves the ZC3H8-KMT2A record as PSI-MI MI:1314 proximity-dependent biotin identification, MI:1060 spoke expansion, ZC3H8 experimental role MI:0496 bait and KMT2A MI:0498 prey, MI-score 0.27, host taxid:9606(human-k_562), IMEx IM-30059, publication PMID 39251607.

   IntAct molecular interaction database (EMBL-EBI), PSICQUIC MITAB 2.7, pubid:39251607, retrieved 2026-09-23 2026
   ▸What this evidence cannot show

   Retrieved live 2026-09-23 by paginating PSICQUIC to exhaustion: 19,403 rows fetched against an endpoint-declared count of 19,403. Rule 93: PSICQUIC is a floor relative to IntAct REST and a REST query on this pair was not run. Spoke expansion means the binary ZC3H8-KMT2A pair was never measured.

   ▸Evidence that argues against this (1)

   • MI-score 0.27 is the deposition-wide value on every row in this file and carries no pair-specific information. source 2026
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

   In IM-30059 ZC3H8 recovered 152 of 2,681 human preys, ranking 40th of 50 baits by reach against a panel median of 326, while KMT2A is recovered by 25 of the 50 baits; under a null holding both the bait's reach and the prey's recoverability, ZC3H8 recovering KMT2A has p = 0.185, which is NOT RESOLVED under the pre-registered thresholds.

   analyses/interactome-tail-size-and-abundance-adjudication/ - orientation.py, pair_null.py, adjudication.json (this repository), pre-registered in PREREGISTRATION.md 2026
   ▸What this evidence cannot show

   20,000 draws, seed 20260923. The null assumes preys are drawn independently given their degrees, which is false when baits share a complex; that makes it anti-conservative. NOT RESOLVED is an honest non-answer, not a soft promotion - this beat writes ZC3H8 for complex membership and cell of origin, not for this p-value.

   ▸Evidence that argues against this (1)

   • A both-margins null rewards selective baits. ZC3H8's relative selectivity (152 preys, 40th of 50) is why its p is as low as 0.185 rather than the 0.70 that the widest bait reaching the same prey receives. A reader should treat 0.185 as 'this bait did not label everything', not as evidence of contact. source 2026
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt Q8N5P1 is 291 aa with three C3H1-type zinc fingers at residues 191-218, 220-247 and 248-271 and disordered regions at 1-26, 51-75 and 93-179, and assigns subcellular location Nucleus with ECO:0000269 experimental evidence citing PMID 23932780.

   UniProtKB Q8N5P1 (ZC3H8_HUMAN) 2026
   ▸What this evidence cannot show

   Fetched live 2026-09-23. Rule 91 applies in the good direction here: the ECO-coded citation is the little elongation complex paper, which does contain immunofluorescence, so the pointer and the fact coincide - which is not the norm and is worth stating.

   ▸Evidence that argues against this (1)

   • Three tandem CCCH zinc fingers are an RNA-binding module. UniProt and HPA both annotate ZC3H8 as RNA-binding, so nuclear residence does not by itself imply a chromatin or transcription-factor role, and the complex assignment is what carries that claim. source 2026
5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Using Drosophila and mammalian systems, Hu et al. provide genetic and molecular evidence that the little elongation complex - comprising ELL, ICE1, ICE2 and ZC3H8 - functions in at least two phases of RNA Pol II snRNA gene transcription: an initiation step requiring the ICE1 subunit and an elongation step requiring ELL.

   The little elongation complex functions at initiation and elongation phases of snRNA gene transcription. · Hu D, Smith ER, Garruss AS, Mohaghegh N, Varberg JM, Lin C, Jackson J, Gao X, Saraf A, Florens L, Washburn MP, Eissenberg JC, Shilatifard A · Mol Cell 2013
   PMID 23932780DOI
   ▸What this evidence cannot show

   Abstract read; full text not read. The abstract assigns functions to ICE1 and ELL specifically and does NOT assign a step to ZC3H8, so ZC3H8's role within LEC is membership, not a demonstrated mechanistic step. Work is in Drosophila salivary gland and HCT116, neither of which is a haematopoietic cell.

   ▸Evidence that argues against this (1)

   • No experiment in this paper tests whether ZC3H8 is required for LEC function; the two phases described are attributed to ICE1 and ELL. An entry that reads ZC3H8 as a functional LEC component is extrapolating from co-purification. source 2013
6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   The human 7SK snRNP - 7SK snRNA, MePCE and LARP7 - functions as a canonical transcription factor that, with the little elongation complex comprising ELL, Ice1, Ice2 and ZC3H8, promotes transcription of RNA Pol II-specific spliceosomal snRNA and snoRNA genes; ChIP and ChIRP show all 7SK snRNP components enriched on those genes, and depletion of 7SK snRNA or Larp7 disrupts LEC integrity, inhibits Pol II recruitment and reduces nascent snRNA and snoRNA synthesis.

   The 7SK snRNP associates with the little elongation complex to promote snRNA gene expression. · Egloff S, Vitali P, Tellier M, Raffel R, Murphy S, Kiss T · EMBO J 2017
   PMID 28254838DOI
   ▸What this evidence cannot show

   Abstract read; full text not read. Work is in HeLa cells. The abstract does not report which LEC subunit contacts the 7SK snRNP, so the ZC3H8-7SK relationship is complex-level and not a demonstrated contact.

   ▸Evidence that argues against this (1)

   • 7SK snRNP is best known in this project as the reservoir that sequesters P-TEFb away from the super elongation complex. Its role here is the opposite in sign - a positive transcription factor at snRNA genes - so citing 7SK as a shared node between LEC and SEC biology conflates two different activities of the same particle. source 2017
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Fliz1 (fetal liver zinc-finger protein 1) was identified by differential-display RT-PCR on fractionated murine E12 fetal liver cells as a novel transcript encoding a 305-residue nuclear protein with a charged domain and three putative C3H-type zinc fingers; its expression was detected in discrete cell foci in the fetal liver and in Lin-/cKit+ cells, and nuclear localisation studies showed Fliz1 is targeted to the nucleus.

   Transcripts of Fliz1, a nuclear zinc finger protein, are expressed in discrete foci of the murine fetal liver. · Dahm K, Nielsen PJ, Müller AM · Genomics 2001
   PMID 11318609DOI
   ▸What this evidence cannot show

   Abstract read; full text not read. This is a 2001 mouse expression study: differential display, in-situ foci and a nuclear-targeting assay. It establishes an expression pattern, not a function, and nothing in it is haematopoietic phenotype data. Mouse Fliz1 is 305 aa and human ZC3H8 is 291 aa; orthology is assumed from the symbol assignment and was not independently checked here.

   ▸Evidence that argues against this (1)

   • The only functional in-vivo study of a Zc3h8 orthologue reports something unrelated to haematopoiesis: a zebrafish point mutant (H353Q) causes liver, gut and exocrine pancreas degeneration through de-repression of NF-kB-mediated inflammation, rescued by suppressing NF-kB signalling. On that evidence Zc3h8's conserved job is inflammatory restraint in digestive organs, not snRNA transcription or blood. Zou Q et al. 2018
8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   PubMed returns zero records for (ZC3H8 OR Fliz1) AND KMT2A in titles and abstracts and zero for the same names against MLL, against a total literature of 12 records for ZC3H8 or Fliz1 anywhere in a title or abstract.

   NCBI PubMed esearch via scripts/pubmed_safe.py, run 2026-09-23; querytranslations recorded: ("ZC3H8"[Title/Abstract] OR "Fliz1"[Title/Abstract]) AND "KMT2A"[Title/Abstract] and the same with "MLL"[Title/Abstract] 2026
   ▸What this evidence cannot show

   Both zeros carry a non-empty querytranslation and a warninglist reading 'No items found.'. NAME LIST TRIED: ZC3H8, Fliz1, ZC3HDC8 - and PubMed SILENTLY DROPPED ZC3HDC8 from the translation, returning only the first two terms, so the previous approved symbol contributed nothing to any of these searches. Bounded by titles and abstracts only.

   ▸Evidence that argues against this (1)

   • A twelve-paper literature means the absence is uninformative about biology: nobody has looked at ZC3H8 in connection with anything much. This is a statement about the field's attention, not about the protein. source 2026
9. E9moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   The Human Protein Atlas assigns ZC3H8 a main subcellular location of nucleoplasm with nuclear bodies as an additional location, reliability 'Supported', classes it as an essential protein with molecular function repressor and RNA-binding, and lists transcription regulation and apoptosis among its biological processes.

   Human Protein Atlas v25.1, proteinatlas.json.gz record for ZC3H8 (ENSG00000144161), retrieved 2026-09-23 2026
   ▸What this evidence cannot show

   Antibody-based immunofluorescence in a small cell-line panel, not in haematopoietic cells. HPA's 'nuclear bodies' class does not identify which nuclear body; this entry does NOT claim Cajal bodies despite the snRNA-gene connection, because the data do not say so.

   ▸Evidence that argues against this (1)

   • 'Supported' is the middle reliability tier, meaning the localisation is consistent with but not independently confirmed beyond the antibody used. An additional-location call at that tier is the weakest kind of subnuclear statement in the resource. source 2026
10. E10moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In DepMap as recorded by this graph's little elongation complex entry, ZC3H8 has a Chronos mean of -0.775 with 90.8% of lines depleted and a KMT2A-selectivity difference of +0.126, against ELL's -1.302 and 94% depleted, ICE1's -0.773 and ICE2's -0.607.

    protein-little-elongation-complex (this graph), data.subunits 2026
    ▸What this evidence cannot show

    Quoted from an existing entry in this repository and NOT re-fetched from DepMap by this beat, so it carries that entry's release and fetch date, neither of which is recorded there. Rule 83: a DepMap number needs its release. Re-pull before using the figure as a live quantity.

    ▸Evidence that argues against this (1)

    • The KMT2A-selectivity difference is POSITIVE (+0.126), meaning KMT2A-rearranged lines are if anything LESS dependent on ZC3H8 than other lines. A broadly required gene with anti-selectivity in the arm of interest is the opposite of a fusion-specific dependency, and that cuts directly against reading the BioID row as functionally meaningful. source 2026

• part of →The little elongation complex (ELL + ICE1 + ICE2 + ZC3H8) — the other place ELL works, and why ELL's pan-essentiality is probably not about the fusion

  the fourth LEC subunit (ELL, ICE1, ICE2, ZC3H8) and the only one that had no entry of its own

• related to →KMT2A / MLL1 — the gene that breaks

  ZC3H8 bait / KMT2A prey, one MI:1314 BioID2 spoke row, IM-30059, K562; p = 0.185, NOT RESOLVED

• co-occurs with →ELL — rank 7 on selectivity and the deepest common-essential in the top ten, with one NMR fragment to its name

  co-subunits of the little elongation complex; ELL is also the 3' partner of fusion-kmt2a-ell

• co-occurs with →ICE1 — the 2,266-residue scaffold of the little elongation complex, the subunit that acts at initiation, and zero papers connecting it to leukaemia of any kind

  co-subunits of LEC; the initiation step is assigned to ICE1 and no step is assigned to ZC3H8

• co-occurs with →ICE2 — the fourth LEC subunit, the one with no assigned step, no structure, and no leukaemia literature

  co-subunits of LEC

• depends on →The 7SK snRNP - a stable RNA core with a reversibly docked kinase, which is why the reservoir is a switch and not a sink

  7SK snRNP associates with LEC at snRNA genes; depleting 7SK snRNA or LARP7 disrupts LEC integrity

• expressed in →Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL

  Fliz1 was discovered by differential display on murine E12 fetal liver and detected in discrete foci and in Lin-/cKit+ progenitors

• related to →Plain-English: what transcription elongation is, and why a traffic light explains this leukemia

  LEC acts at the elongation phase of Pol II snRNA gene transcription

• supports →Prey recovery in the two BioID depositions tracks SIZE and not abundance - and the interactome tail was being scored on the wrong side of the pair, because every one of the 22 partners is the BAIT and every core protein is the PREY

  a relatively selective bait (152 of 2,681 preys, 40th of 50) whose KMT2A row is still NOT RESOLVED at p = 0.185

• part of →The 50-RBP BioID2 proximity map in K562 - the first modern proximity dataset this graph can reach, and AFF1 is in it as prey

  one of the 50 BioID2 baits in IM-30059

• ← co-occurs withDDX55 - a large-subunit rRNA helicase that is nucleolar by imaging and nucleoplasmic by its own founding paper, and the narrowest RBP bait to reach KMT2A after DDX52

  two of the three narrowest baits in IM-30059 that reach KMT2A (131 and 152 preys, p = 0.162 and 0.185)