ELL3 — the third ELL paralogue, which marks enhancers and recruits SEC rather than sitting inside it
also called ELL3 · RNA polymerase II elongation factor ELL3 · Ell3
ELL3 is the third member of a family of three near-identical elongation factors, and it is the odd one out: instead of joining the machine, it sits on enhancers ahead of time and calls the machine in when a signal arrives. It is not a part of the KMT2A fusion complex.
The same thing, for a scientist
ELL3 (Q9HB65, 397 aa) is the smallest of the three ELL-family RNA Pol II elongation factors (ELL 621 aa, ELL2 640 aa). In embryonic stem cells ELL3 occupies enhancers, including inactive and poised enhancers, and its enhancer association is required both for proper promoter-proximal Pol II occupancy at developmentally regulated genes and for **recruitment of the super elongation complex to those loci after a differentiation signal**. That is a different job from the one ELL and ELL2 do: the primary source positions ELL3 as an upstream enhancer mark that calls SEC in, not as an interchangeable occupant of the SEC ELL slot. This entry therefore also serves as a correction to the framing used elsewhere in this graph, where ELL, ELL2 and ELL3 are described as interchangeable parts filling one slot — that is true of ELL and ELL2 on the published biochemistry, and is not established for ELL3. ELL3 is not a KMT2A::AFF1 interactor and shows no dependency of any kind (mean -0.175 across 1,208 lines, 2.5% depleted, KMT2A-selectivity -0.030).
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
What the primary source actually says
In embryonic stem cells, Ell3 occupies enhancers. Its association with enhancers is required for setting up proper Pol II occupancy at promoter-proximal regions of developmentally regulated genes, and for the recruitment of the super elongation complex to those loci following differentiation signals. Ell3 binding to inactive or poised enhancers is essential for stem-cell specification, and Pol II and Ell3 were also detected in germ-cell nuclei 1.
Read carefully, this places ELL3 upstream of SEC in a recruitment relationship. It does not say ELL3 is a SEC subunit, and it does not say ELL3 substitutes for ELL or ELL2 in the complex. This matters because the standard diagram of SEC shows one ELL-family slot with three interchangeable occupants, which invites an inference this paper does not support for the third one.
Method: ChIP-seq occupancy, knockdown with Pol II occupancy and SEC-recruitment readouts, differentiation assays in mouse ES cells 1. Shown for: wild-type biology in ES and germ cells. No KMT2A fusion protein is tested. Which part of the fusion: none. ELL3 is not a member of the KMT2A::AFF1 interactome.
The three-paralogue picture, completed
With this entry the ELL family is fully represented in the graph and the spread is extreme 2:
| Gene | mean gene effect | % lines depleted | KMT2A-selectivity | role as published |
|---|---|---|---|---|
| ELL | -1.30 | 94% | -0.18 | SEC ELL slot; common-essential |
| ELL2 | -0.06 | 1.0% | -0.01 | SEC ELL slot; dispensable |
| ELL3 | -0.18 | 2.5% | -0.03 | enhancer mark that recruits SEC |
Three proteins of the same family, one required by almost every cell and two required by almost none, and — on this paper — not all doing the same job. Any argument of the form 'the fusion needs an ELL-family protein, therefore the ELL family is a target' has to survive that table, and it does not: the only pan-essential member is the one whose essentiality is least likely to be about the fusion.
ELL3's enhancer biology is nonetheless the most interesting thing about it for this project, because KMT2A fusions bind a distinct enhancer repertoire and because the claim here is that ELL3 determines where SEC gets recruited. Whether ELL3 pre-marks the enhancers that a KMT2A fusion later occupies is a question nobody has asked.
| uniprot | Q9HB65 |
|---|---|
| gene symbol | ELL3 |
| length AA | 397 |
| protein name | RNA polymerase II elongation factor ELL3 |
| alphafold ID | AF-Q9HB65-F1 |
| accession resolution | UniProt query gene_exact:ELL3 AND organism_id:9606 AND reviewed:true; primary gene name read back as ELL3 and length 397 confirmed |
| interaction evidence class | ChIP-seq occupancy, knockdown with Pol II and SEC recruitment readouts, ES differentiation assays |
| shown for fusion | false |
| contact on kmt2a aff1 | none |
| relationship to sec | recruits SEC to enhancer-primed loci; not shown to be a SEC subunit in the primary source |
| druggability | Not a target. Entered to complete the ELL family and to flag that the 'three interchangeable paralogues' framing is not established for ELL3. |
ell family — the numbers behind the chart
[
{
"gene_symbol": "ELL",
"uniprot": "P55199",
"length_aa": 621,
"role": "SEC ELL slot; DepMap common-essential"
},
{
"gene_symbol": "ELL2",
"uniprot": "O00472",
"length_aa": 640,
"role": "SEC ELL slot; dispensable"
},
{
"gene_symbol": "ELL3",
"uniprot": "Q9HB65",
"length_aa": 397,
"role": "enhancer occupancy; required for SEC recruitment after differentiation signals"
}
]essentiality
{
"depmap_common_essential": false,
"chronos_mean": -0.175,
"n_lines": 1208,
"fraction_lines_depleted": 0.0248,
"chronos_mean_kmt2a_rearranged": -0.1535,
"chronos_mean_other_leukemia": -0.1239,
"kmt2a_selectivity_difference": -0.0296,
"n_kmt2a_rearranged_lines": 11,
"n_other_leukemia_lines": 43,
"benchmark_men1_difference": -0.8656
}- ELL3 is required for stem-cell specification in the published model; anything that blocked it would risk a developmental rather than a leukemia-specific effect, in a patient population of infants.
- The ELL family's dependency spread means an ELL-directed strategy either hits the pan-essential member and is toxic, or hits the dispensable members and does nothing.
- Does ELL3 pre-mark the enhancers that KMT2A fusions later occupy? The fusion's enhancer repertoire is known and ELL3's ES-cell enhancer repertoire is known; nobody has intersected them in a haematopoietic setting.
- Is ELL3 physically a SEC subunit or only a recruiter? The two published framings have never been reconciled in one experiment.
- Is ELL3 expressed in fetal liver or pro-B progenitors at all? If the ES-cell biology does not transfer, this entry is purely a completeness record.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Ell3 occupies enhancers in embryonic stem cells; its enhancer association is required for proper Pol II occupancy at promoter-proximal regions of developmentally regulated genes and for recruitment of the super elongation complex to those loci following differentiation signals; Ell3 binding to inactive or poised enhancers is essential for stem cell specification; and Pol II and Ell3 are present in germ cell nuclei.
The RNA Pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. · Lin C, Garruss AS, Luo Z, Guo F, Shilatifard A · Cell 2012What this evidence cannot show
Abstract read in full; not full text. Mouse embryonic stem cells and germ cells — not haematopoietic, not human leukemia, and no KMT2A fusion anywhere in the study. The abstract does not state whether Ell3 is physically part of SEC; it describes recruitment of SEC, which is a different relationship, and this entry does not go beyond that wording.
Evidence that argues against this (1)
- This entry's distinction between ELL3 as an enhancer mark and ELL/ELL2 as SEC subunits rests on the wording of one abstract. Other work in the SEC field lists ELL3 among the ELL-family proteins that can occupy the SEC ELL slot, and the two readings are not formally incompatible - a protein can both mark enhancers and enter a complex. The strong form of the claim, that ELL3 does not occupy the SEC slot, is NOT established here and should not be cited as if it were. Luo Z et al. 2012
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
ELL3 has DepMap mean gene effect -0.175 across 1,208 lines with 2.5% of lines depleted, mean -0.1535 in 11 KMT2A-rearranged leukemia lines against -0.1239 in 43 other leukemia lines (difference -0.030); MEN1 in the same lines is -0.866.
DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API, with KMT2A-rearrangement status from Cellosaurus; per-gene recomputation for this beat · Broad Institute DepMap; Cellosaurus; Open Targets Platform; analysis run by this project · Database and derived analysis 2026What this evidence cannot show
DepMap release version not stated by the API. The ELL and ELL2 values quoted in the comparison table are carried from existing graph entries (gene-ell2, protein-ell-eaf-module) computed in an earlier cycle with a slightly different line set, so the three rows are not exactly like-for-like on the selectivity column.
Evidence that argues against this (1)
- −0.1535 against −0.1239 is a difference of 0.03 in the wrong direction for significance, with 2.5% of lines depleted. This is a null. Oncofusion knowledge graph (internal analysis) 2026
ELL-family paralogue; ELL is common-essential, ELL3 is not, and their published jobs differ
- related to →ELL2 — a SEC subunit that almost no cell needs, next to a paralogue almost every cell needs
completes the ELL family; the 'three interchangeable paralogues' framing is not established for ELL3
ELL3 enhancer occupancy is required for SEC recruitment after differentiation signals