Oncofusion

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Non-codingstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q107-break-machinery-deposition

The KMT2A exon-11 CTCF/cohesin summit, measured: GRCh38 chr11:118,488,694 (CTCF) and chr11:118,488,677 (RAD21), 17 bp apart, both inside canonical exon 11

also called the measured exon-11 summit · chr11:118,488,694 · the KMT2A loop-anchor summit · hg19 chr11:118,359,409

This project had an interval for the CTCF landing site inside KMT2A but never a single base. Reading the published raw signal gives one: the peak of CTCF binding is at base 118,488,694 of chromosome 11, and the cohesin ring peaks 17 bases away, both inside the short piece of gene the whole argument is about.

The same thing, for a scientist

`genome-kmt2a-exon-11-ctcf-site` records this element as an ENCODE cluster interval, and `ana-kmt2a-bcr-ctcf-site-coordinate-overlap` closes with *"the one thing this analysis still cannot give is the CTCF peak SUMMIT and its motif orientation"*. **The summit is now measured**, from Canela 2019's deposited HCT116 ChIP-seq: **CTCF at GRCh37 chr11:118,359,409 = GRCh38 chr11:118,488,694**, **RAD21 at GRCh37 chr11:118,359,392 = GRCh38 chr11:118,488,677** [E1]. The peak footprint runs GRCh37 chr11:118,359,150-118,359,700 (~550 bp) with a FWHM of roughly 200 bp, and its rank is the top **0.02%** of chr11 - 176 of 918,411 147-bp bins exceed the CTCF value, 185 exceed the RAD21 value [E1]. **Both summits lie inside canonical *KMT2A* exon 11** (GRCh38 chr11:118,488,614-118,488,760), at +80 bp and +63 bp from the exon start, and inside the 300-bp patient break-prone window of PMID 34405474 (GRCh38 chr11:118,488,500-118,488,800). **The functional cut point is 3,833 bp away** (GRCh38 chr11:118,484,861|862) and carries 1.20x-genome-mean CTCF and 0.27x-genome-mean RAD21 - i.e. nothing [E1].

Go deeper
The coordinate set, one frame, both builds
featureGRCh38GRCh37/hg19width
CTCF summit (measured)chr11:118,488,694chr11:118,359,4091 bp
RAD21 summit (measured)chr11:118,488,677chr11:118,359,3921 bp
peak footprint (measured)chr11:118,488,435-118,488,985chr11:118,359,150-118,359,700~550 bp
canonical exon 11 (ENST00000534358)chr11:118,488,614-118,488,760chr11:118,359,329-118,359,475147 bp
ENCODE CTCF+RAD21+SMC3 clusterchr11:118,488,159-118,489,206chr11:118,358,874-118,359,9211,048 bp
patient break-prone window (PMID 34405474)chr11:118,488,500-118,488,800chr11:118,359,215-118,359,515300 bp
functional cut point (canonical intron 9/exon 10)chr11:118,484,861 | 118,484,862chr11:118,355,576 | 118,355,577junction
KMT2A genechr11:118,436,492-118,526,832chr11:118,307,205-118,397,53990,335 bp

GRCh38 - GRCh37 = 129,285 bp, constant across this span, established by three separate Ensembl map/human/GRCh38/.../GRCh37 calls and confirmed arithmetically 2.

CTCF summit to cut point: 3,833 bp. RAD21 summit to cut point: 3,816 bp. (Q105's figure of 3,752 bp is the distance from the cluster start to the cut point; the summit-based distances are slightly larger and are the ones to quote now that a summit exists.)

CTCF summit to the centre of the patient window (GRCh38 118,488,650): 44 bp.

What is still not measured

Motif orientation is still unknown, and it is the property that decides whether this element is a loop anchor's left or right side. A bigWig gives coverage, not a motif call, and neither Canela deposit contains a CTCF motif annotation or a peak-summit file. The route to orientation is the JASPAR/HOCOMOCO CTCF PWM scanned over the 550-bp footprint sequence - a desk job, not a compute job, and this beat did not do it. It should be the next thing anyone does with this coordinate, because Canela 2017's whole argument turns on convergent CTCF motif orientation at anchors.

Occupancy in a haematopoietic cell IS now measured, and it agrees to the base. This summit is from HCT116, a colorectal carcinoma line - but ENCODE CTCF ChIP in GM12878, a human B-lymphoblastoid line, puts its maximum at the identical base, GRCh38 chr11:118,488,694 (ENCFF734CUT, ENCSR000AKB), with a second GM12878 experiment at chr11:118,488,671 and GM12878 RAD21 at chr11:118,488,664 - a 30 bp spread across three independent experiments in two cell types. The exon reads 113x and 135x genome mean in the two GM12878 CTCF files, 7 to 27 times stronger than the H19/IGF2 imprinting control region in the same files. See absence-no-human-ctcf-or-cohesin-occupancy-measurement-in-a-blood-cell-at-kmt2a, which enumerates the absence in the dispute's own deposits and then closes it. What is still unmeasured is a B-cell PRECURSOR, a CD34-positive progenitor or any fetal cell - ENCODE has no CD34-positive common-myeloid-progenitor CTCF track with GRCh38 fold-change output.

And a caution on precision. A 1-bp summit from a ~200 bp FWHM ChIP peak with n = 1 is a maximum of a smooth function, not a resolved binding position; the honest precision is roughly +/-25 bp. The 17-bp CTCF-RAD21 offset is within that and should not be interpreted as a real spatial relationship.

Facts and figures
elementCTCF/cohesin loop-anchor site inside canonical KMT2A exon 11
ctcf summit grch38chr11:118488694
rad21 summit grch38chr11:118488677
ctcf summit grch37chr11:118359409
rad21 summit grch37chr11:118359392
footprint grch37chr11:118359150-118359700
footprint bp550
positional precision bp25
chr11 rank ctcftop 0.02% (176 of 918,411 147-bp bins above)
chr11 rank rad21top 0.02% (185 of 918,411 147-bp bins above)
cell type measuredHCT116 (human colorectal carcinoma)
distance ctcf summit to cut point bp3833
distance rad21 summit to cut point bp3816
distance ctcf summit to patient window centre bp44
motif orientationNOT MEASURED - requires a PWM scan of the footprint sequence, not done here
grch38 minus grch37 offset bp129285
transcriptENST00000534358
rpe summit measured cycle 59
{
  "control_tracks": [
    "GRCh38 118,488,727.7",
    "GRCh38 118,488,662.3"
  ],
  "sikdm3b_tracks": [
    "GRCh38 118,488,760.6",
    "GRCh38 118,488,676.4"
  ],
  "method": "signal-weighted CENTROID over the element rather than an argmax, because the CTCF tracks are 200 bp binned and an argmax would return a bin label",
  "agreement_with_the_prior_measurement": "control pair within +/-34 bp of 118,488,694",
  "verdict": "Gray's 'exon 11 CTCF site' IS Ensembl canonical exon 11. The graph's CTCF adjudication is confirmed in the founding paper's own cell type and the last route by which it could have been wrong is closed."
}
How this could bite us back
  • A precise coordinate invites precise interventions - base editing the CTCF motif, for instance - and the direction of effect is genuinely unknown: Gray 2023 predicts that weakening this site RAISES KMT2A rearrangement while the fragility literature predicts it lowers breakage. An editing experiment here could increase leukaemogenic risk.
  • The summit is from a colorectal line and will be quoted as 'the KMT2A CTCF site'. The cell type should travel with the coordinate every time.
Still open
  1. What is the CTCF motif orientation at this summit? A JASPAR/HOCOMOCO PWM scan of the 550-bp footprint would give it, and Canela 2017's convergent-orientation argument makes it load-bearing. It is a desk job and it is undone.
  2. Where is Gray 2023's own CTCF summit in RPE cells? GSE210480's four CTCF bigWigs are now readable with the same tooling, and the answer decides whether Gray's protective site and this element are the same object.
  3. Does the summit shift between cell types? CTCF summits are usually stable, but the element's break maximum shifted by up to 144 bp across TK6, K562 and CD34+, so a per-cell-type occupancy comparison is not idle.
Every source behind this entry (2)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset

    In Canela 2019's deposited HCT116 ChIP-seq bigWigs (GEO GSE129526), the CTCF signal maximum over the ENCODE CTCF+RAD21+SMC3 cluster is at GRCh37 chr11:118,359,409 and the RAD21 maximum at GRCh37 chr11:118,359,392 - both inside canonical KMT2A exon 11 - with a footprint of roughly GRCh37 chr11:118,359,150-118,359,700, region means of 84.94x (CTCF) and 104.12x (RAD21) the respective file's genome-wide mean over the 147-bp exon, ranking in the top 0.02% of chr11 147-bp bins (176 and 185 of 918,411 bins above them), against 1.20x and 0.27x over the functional cut point at GRCh37 chr11:118,355,076-118,356,077.

    GEO GSE129526 samples GSM3714940 (ChIP_seq_CTCF_HCT116), GSM3714939 (ChIP_seq_RAD21_HCT116) and GSM3714941 (ChIP_seq_INPUT_HCT116) - deposited bigWig tracks read at base resolution over HTTP range requests with pybigtools 0.3.0, 2026-09-22 · Canela A, Maman Y, Huang SN, Wutz G, Tang W, Zagnoli-Vieira G, Callen E, Wong N, Day A, Peters JM, Caldecott KW, Pommier Y, Nussenzweig A · NCBI GEO (data accompanying Mol Cell 75:252-266.e8) 2019
    PMID 31202577DOI
    What this evidence cannot show

    n = 1 per target, no replicate, so the summit is a single-experiment maximum. The peak FWHM is roughly 200 bp, so the honest positional precision is about +/-25 bp and the 17-bp CTCF-RAD21 offset is not resolvable. HCT116 is a near-diploid MSI colorectal carcinoma line; this is not occupancy in a haematopoietic cell. Both samples are mis-annotated in GEO as Mus musculus/mm10 (the files are human hg19) and all three ChIP samples share one antibody catalogue number, Millipore 07-729, which is an anti-RAD21 reagent - so the CTCF track's reagent identity rests on the sample title. The input track reads 2.67x its own genome mean over this exon, indicating an elevated coverage baseline that the fold-over-input figures absorb but the fold-over-genome-mean figures do not.

    Evidence that argues against this (1)
    • The competing coordinate source is Gray 2023's own CTCF ChIP-seq in RPE cells, deposited as four bigWigs in GSE210480 and still unread. If its summit in RPE is at GRCh37 ~118,355,600 rather than ~118,359,400, then Gray's 'exon 11' is DCAL exon 11 (canonical exon 10), the two literatures describe two elements 3.8 kb apart, and this summit - while still the correct summit for the ENCODE cluster - would not be Gray's protective site. That check remains open and is now cheap, because the tooling objection that blocked it has been removed. **RETIRED CYCLE 59 - THE CHECK IS RUN AND THE ANSWER IS NO.** Signal-weighted centroids over the element in Gray's own RPE CTCF tracks put the summit at GRCh38 118,488,727.7 and 118,488,662.3 in the two control tracks and 118,488,760.6 and 118,488,676.4 in the two siKDM3B tracks. All four are inside canonical exon 11, the control pair is within +/-34 bp of the independently measured 118,488,694, and every track is 3,801-3,899 bp from the DCAL cut point. The only rival element carries 1.27x-chr11-mean CTCF in the same tracks - no peak for the authors to have meant. Four experiments, three cell types (HCT116, GM12878 x2, RPE), ~100 bp spread. NCBI Gene Expression Omnibus 2024
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    The GRCh38-to-GRCh37 offset across this locus is exactly 129,285 bp and constant: GRCh38 chr11:118,488,159-118,489,206 maps to GRCh37 chr11:118,358,874-118,359,921, GRCh38 chr11:118,488,614-118,488,760 to GRCh37 chr11:118,359,329-118,359,475, and GRCh38 chr11:118,484,861|862 to GRCh37 chr11:118,355,576|577, all plus-strand with widths preserved; KMT2A occupies GRCh37 chr11:118,307,205-118,397,539 and ENST00000534358 is the canonical transcript in GRCh37 as well as GRCh38.

    What this evidence cannot show

    For the 1,048-bp cluster and the 147-bp exon the endpoint returns TWO mappings with identical coordinates, one onto chromosome 11 and one onto the alternative scaffold HG122_PATCH; for the 2-bp cut point it returns only the chromosome-11 mapping. Filter on seq_region_name == '11'. A constant offset over 4 kb does not license the same arithmetic elsewhere on chr11.

    Evidence that argues against this (1)
    • The GRCh38 KMT2A gene span given in the table (chr11:118,436,492-118,526,832) was derived by adding the 129,285 offset to the GRCh37 span rather than looked up in GRCh38 directly, which is exactly the extrapolation this item's own caveat warns against - a gene-length span crosses more potential assembly differences than a 4 kb window. Treat the gene-span row as approximate and re-look-up before quoting it. Ensembl REST API 2026
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