Other HMG-box
This entry holds the HMG-box factors that are neither SOX nor TCF/LEF: HMG20A (iBRAF), HMG20B (BRAF35) and BBX (bobby sox homolog). They share only the fold. HMG20A and HMG20B are paralogous subunits of chromatin complexes - HMG20B of the LSD1-CoREST-HDAC complex that keeps neuronal genes off in non-neuronal cells, HMG20A of KMT2A/MLL complexes that turn them on - so their genomic distribution is largely set by whichever partner recruits the complex. BBX is a poorly characterized protein that groups phylogenetically with CIC rather than with SOX. The three measured motifs are unrelated to each other and to the SOX core, and this is the least coherent family in the HMG class; a hit here should be treated as a lead, not an identification.
The factors
Three proteins are collected here, and what they have in common is a single HMG box, not a site. HMG20B, originally named BRAF35 (BRCA2-associated factor 35), is a core subunit of the BHC complex that pairs LSD1 (KDM1A) and CoREST with histone deacetylases and represses neuronal genes in non-neuronal cells 12032298. HMG20A, its paralogue, was named iBRAF for inhibitor of BRAF35: it opposes that complex and instead recruits KMT2A/MLL to drive neuronal gene expression 16227968, and it is also found in a KMT2A-associated PHF5A-PHF14-HMG20A-RAI1 subcomplex 37709746. HMG20B has a separate mitotic function that depends on its interaction with the BRC repeats of BRCA2 21399666. Both are broadly expressed. BBX is a larger, much less studied protein, broadly expressed with enrichment in the central nervous system, which phylogenetic analysis places with CIC (capicua) in an HMG-box subfamily distinct from both SOX and TCF/LEF 25079045. The important structural point is that most HMG boxes are architectural rather than sequence-reading domains: the HMGB1/HMGB2 type binds and bends DNA with little sequence preference, and only a minority of the superfamily - SOX, TCF/LEF, CIC and a few others - has demonstrable sequence specificity 7774012. Nothing published establishes that HMG20A or HMG20B selects a specific sequence in cells.
The motif
There is no single consensus for this family, which is why none is given. The four models here disagree with each other; cohesion is 0.45, the lowest of the HMG-class families. BBX gives the most informative model, and it is the family medoid: CIS-BP reports TGAACRVCGTTCA (15.1 bits), the human HT-SELEX matrix of Yin et al. 2017, and the Vierstra archetype AC0363 reports TGAACRNYGTTCA (15.8 bits) 25215497,28473536,32728250. These are the same 13-base element - an inverted repeat, since TGAAC and GTTCA are reverse complements, with three variable bases between them - but not two measurements of it: Vierstra archetypes are clusters of models compiled from existing collections 32728250, so AC0363 most likely re-renders the same in vitro data. The half-site resembles the TGAAT half of the dimeric, palindromic sites that appear in SOX models (Vierstra TGAATGTGCAGTCA, HOCOMOCO SOX1 TGAATANCATTCAT), differing at one position, which is consistent with BBX reading DNA in the same general way as other sequence-specific HMG boxes. HMG20A's single HOCOMOCO model, HM20A.H14CORE.0.SB.A, reads TCCCTAGGC (11.5 bits); its fourth field carries S, so it rests on HT-SELEX rather than on ChIP, and it is graded A. CCTAGG is itself palindromic but bears no relation to the SOX or TCF/LEF core. The HMG20B model, CIS-BP M02487_2.00, is ATTATAT (10.5 bits) and is inferred from the mouse protein at 94% DNA-binding-domain identity 25215497; a short AT-rich string of this kind is what a non-sequence-specific HMG box tends to produce in a selection experiment, and it should not be read as a recognition sequence.
Where it acts
For HMG20A and HMG20B the practical answer is: wherever the complex goes. LSD1-CoREST-HDAC is recruited to neuronal gene promoters largely by REST binding its own RE1/NRSE element 12032298, and KMT2A complexes are recruited by their own targeting subunits; HMG20A and HMG20B come along as subunits. Locations reported for them therefore track partner occupancy - neuronal gene promoters, pancreatic islet regulatory regions where HMG20A is required for beta cell maturation 29449530, adipocyte loci where HMG20A acts through MEF2C 36142473, and KMT2A targets in pancreatic cancer stem cells 37709746. BBX has been mapped less. Its 13-base palindrome is specific by the standards of this atlas: with two degenerate inner positions, TGAACRVCGTTCA is expected only a few hundred times in a 3.1 Gb genome, against tens of thousands for the nine-base HMG20A model and millions for a bare six-base HMG core.
Biology and disease
HMG20B is required for repression of the neuronal program in non-neuronal cells and for completion of mitosis 12032298,21399666, and its splicing has been implicated in breast cancer 39731153; the HMG20A locus is a genome-wide-association signal for type 2 diabetes, and HMG20A is needed for functional maturity of pancreatic beta cells 29449530, restrains adipogenesis through MEF2C 36142473, and supports the stem- cell state in pancreatic cancer. The HMG20A/HMG20B antagonism is a clean example of two paralogues with the same DNA-binding domain having opposite effects by virtue of the complexes they join. BBX has been linked to phosphate homeostasis through regulation of FGF23 in bone 39482539, and is maternally expressed and CNS-enriched in zebrafish and mouse 25079045. None of the three has an established monogenic human disease.
Reading a hit
Treat this family as a fold, not a motif: the models do not resemble one another and the family cohesion is 0.45. The BBX palindrome is worth taking seriously as a sequence - it is long enough to be rare - but its presence in two databases is not independent confirmation, and the label rests on in vitro selection with no structural or functional follow-up, so "BBX site" is provisional, and because the half-sites resemble those of dimeric SOX sites you should exclude SOX before settling on BBX. An HMG20A match does not license the conclusion that HMG20A occupies the site: the HT-SELEX evidence supports "this protein can bind this sequence", while in cells HMG20A is a passenger in LSD1-CoREST and KMT2A complexes whose distribution is set by REST and other partners, so check for an RE1/NRSE element nearby. The HMG20B model is mouse-inferred and low in information; do not use it to call sites. More generally, a weak AT-rich match labelled with an HMG-box protein is more likely to reflect a shape preference than a recognition sequence.
How this was worked out
- 2002mediumComplex purification and mass spectrometry, chromatin immunoprecipitation, reporter assays12032298
BRAF35 (HMG20B) is purified as a subunit of the BHC complex, which joins LSD1 and CoREST to histone deacetylases and is recruited by REST to the RE1/NRSE element of neuronal genes; a point mutation in the BRAF35 HMG domain blocks REST-mediated repression.
Still open then: The HMG domain mattered for repression, but no sequence preference was defined for BRAF35 itself.
HMG20A, named iBRAF, is shown to antagonize BRAF35: it accumulates at neuronal gene promoters during differentiation, recruits the methyltransferase MLL and raises H3K4 trimethylation, activating the genes BRAF35 helps repress.
HMG20B acquires a function unrelated to transcription: it binds the BRC5 repeat of BRCA2, and its depletion blocks completion of cell division.
- 2017lowHT-SELEX (as compiled in JASPAR and CIS-BP); earlier phylogenetics and expression analysis28473536 25079045
HT-SELEX of human BBX gives a 13-base palindrome, TGAACGCCGTTCA, the only informative model in this group; the CIS-BP BBX model (TGAACRVCGTTCA) is the same matrix. A 2014 phylogenetic analysis had already placed BBX with CIC in an HMG-box subfamily separate from SOX and TCF/LEF.
Still open then: No structure, no genomic occupancy data and no functional test of the proposed BBX site.
- 2018mediumExpression profiling, knockdown in islets and cell lines, chromatin immunoprecipitation, reporter assays29449530
HMG20A is linked to beta cell biology: it is expressed in human and mouse islets, reduced in islets from type 2 diabetic donors, needed for glucose-stimulated insulin secretion, and the diabetes-associated rs7119 variant lowers its expression in a reporter assay.
Clustering human motif collections into archetypes keeps the BBX palindrome as its own archetype, AC0363, rather than folding it into the SOX or TCF/LEF clusters, which is the strongest evidence that it is a distinct element.
Still open then: Archetypes are clustered from the same motif collections, so this is not an independent measurement of the BBX site.
HMG20A is found in a PHF5A-PHF14-HMG20A-RAI1 subcomplex that binds the histone methyltransferase KMT2A in pancreatic cancer stem cells, reinforcing the picture of HMG20A as a complex subunit rather than a site-selecting factor.
The first mammalian loss-of-function phenotype for BBX: Bbx-null and osteocyte-specific Bbx-deleted mice have raised serum FGF23, low serum phosphate and reduced bone mass, and BBX suppresses vitamin D-induced Fgf23 promoter activity.
Still open then: Whether BBX acts at the Fgf23 promoter through its own palindromic site or through its interaction with the vitamin D receptor was not resolved.
Still unresolved
- Whether HMG20A and HMG20B select DNA sequences in cells at all is unresolved: HT-SELEX gives HMG20A a grade-A model for TCCCTAGGC, yet both proteins are documented as subunits of LSD1-CoREST and KMT2A complexes whose placement is set by REST and other targeting factors, and no ChIP-derived motif exists for either.
- How BBX represses FGF23 is open: the mouse work shows both a vitamin D receptor interaction with ubiquitin-dependent BBX degradation and an effect on Fgf23 promoter activity, without establishing whether a BBX site in that promoter is occupied.
Low confidence throughout. This is a fold-defined group with no shared consensus and the lowest cohesion in the HMG class (0.45) across only four models. The BBX 13-base palindrome appears in two databases that most likely share one in vitro source, so they do not confirm each other; it is rare enough to be useful, but rests on in vitro selection alone and its half-sites overlap those of dimeric SOX sites. The HMG20A motif has HT-SELEX support, yet HMG20A acts as a subunit of LSD1-CoREST and KMT2A complexes, so genomic locations attributed to it may belong to REST or another recruiting factor. The HMG20B model is inferred from mouse at 94% DNA-binding-domain identity and is an uninformative AT-rich string.
References
- Hakimi MA, Bochar DA, Chenoweth J, et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A 2002;99:7420-5. PMID 12032298
- Wynder C, Hakimi MA, Epstein JA, et al. Recruitment of MLL by HMG-domain protein iBRAF promotes neural differentiation. Nat Cell Biol 2005;7:1113-7. PMID 16227968
- Lee M, Daniels MJ, Garnett MJ, et al. A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor. Oncogene 2011;30:3360-9. PMID 21399666
- Mellado-Gil JM, Fuente-Martín E, Lorenzo PI, et al. The type 2 diabetes-associated HMG20A gene is mandatory for islet beta cell functional maturity. Cell Death Dis 2018;9:279. PMID 29449530
- Li R, Meng S, Ji M, et al. HMG20A Inhibit Adipogenesis by Transcriptional and Epigenetic Regulation of MEF2C Expression. Int J Mol Sci 2022;23. PMID 36142473
- Mouti MA, Deng S, Pook M, et al. KMT2A associates with PHF5A-PHF14-HMG20A-RAI1 subcomplex in pancreatic cancer stem cells and epigenetically regulates their characteristics. Nat Commun 2023;14:5685. PMID 37709746
- Chen T, Zhou L, Yuan Y, et al. Characterization of Bbx, a member of a novel subfamily of the HMG-box superfamily together with Cic. Dev Genes Evol 2014;224:261-8. PMID 25079045
- Lee SJ, Kim JA, Ihn HJ, et al. The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23. Exp Mol Med 2024;56:2436-2448. PMID 39482539
- Zhong G, Shen Q, Zheng X, et al. CPSF4-mediated regulation of alternative splicing of HMG20B facilitates the progression of triple-negative breast cancer. J Transl Med 2024;22:1149. PMID 39731153
- Werner MH, Huth JR, Gronenborn AM, et al. Molecular basis of human 46X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex. Cell 1995;81:705-14. PMID 7774012
- Weirauch MT, Yang A, Albu M, et al. Determination and inference of eukaryotic transcription factor sequence specificity. Cell 2014;158:1431-1443. PMID 25215497
- Vierstra J, Lazar J, Sandstrom R, et al. Global reference mapping of human transcription factor footprints. Nature 2020;583:729-736. PMID 32728250
- Yin Y, Morgunova E, Jolma A, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 2017;356. PMID 28473536
4 motifs in this family — HOCOMOCO 1 · CIS-BP 2 · Vierstra 1
| motif | database | consensus | bits |
|---|---|---|---|
| AC0363:BBX:Sox | Vierstra | TGAACrnyGTTCA | 15.8 |
| M05763_2.00 | CIS-BP | TGAACrvcGTTCA | 15.1 |
| HM20A.H14CORE.0.SB.ASBA | HOCOMOCO | tcCCTAgGc | 11.5 |
| M02487_2.00Mus musculus 0.94 | CIS-BP | ATTATaT | 10.5 |
HOCOMOCO tags read as assay + quality grade: P ChIP-seq, S HT-SELEX, M methyl-HT-SELEX, G GHT-SELEX, I SMiLE-seq, B PBM; grade A means two or more assay types agreed. A P-only matrix is a record of where the protein was crosslinked, which need not be a sequence it binds itself.
The factors, elsewhere
These entries are written from the primary literature and every citation is checked against PubMed, but this one can still be out of date, too confident, or simply wrong — especially where a motif’s published site and its database matrices disagree. Corrections and additions are welcome, and they are the fastest way to make this page better for everyone.