Ndt80/PhoG-like (C11orf9/MYRF)
This family is named after the budding yeast meiotic activator Ndt80, whose DNA-binding domain defines an immunoglobulin-like fold shared by the human proteins MYRF and MYRFL. MYRF, myelin regulatory factor, is the only well-characterized vertebrate member. It is an endoplasmic-reticulum membrane protein that trimerizes and cleaves itself using a domain related to bacteriophage tailspike proteins; the released N-terminal fragment enters the nucleus and binds DNA. The measured site is the palindromic eight-base TGGTACCA, consistent with binding by a symmetric oligomer. MYRF is required for oligodendrocyte differentiation and for making and maintaining central nervous system myelin, and human MYRF variants cause a cardiac-urogenital syndrome and disorders of sex development.
The factors
The family is defined by a DNA-binding fold, not by a lineage of related regulators. It takes its name from Ndt80, the Saccharomyces cerevisiae transcription factor that is activated at pachytene and turns on roughly 150 middle sporulation genes, including the B-type cyclins, once meiotic recombination is complete 9660952,12411490. The crystal structure of the Ndt80 DNA-binding domain showed an immunoglobulin-like fold, with functional similarities that suggested an evolutionary link to the p53 family 12411490. Human proteins carrying the same Ndt80/PhoG-like domain are MYRF (myelin regulatory factor, formerly C11orf9 or MRF) 19596243 and its paralogue MYRFL, which is poorly characterized. MYRF is unusual for a transcription factor: it is synthesized as a type-2 transmembrane protein in the endoplasmic reticulum, assembles into a homotrimer, and then cleaves itself through an autoproteolytic intramolecular chaperone domain that is related to the corresponding domain of bacteriophage tailspike proteins, the first time that domain was found in a eukaryotic protein 23966832,23966833. Cleavage separates the transmembrane C-terminal region from an N-terminal fragment that carries the DNA-binding domain and a nuclear localization signal 23966833. MYRF expression is essentially restricted to oligodendrocytes in the central nervous system 19596243, with some expression in Schwann cells and other tissues 29446546; it is not a broadly expressed factor.
The motif
All three models in these databases converge on TGGTACCA, an eight-base perfect palindrome, which is what a symmetric trimeric or dimeric binder would be expected to select: the half-site is TGGT, read on both strands. The CIS-BP MYRF model and the Vierstra archetype AC0396 are identical to each other 25215497,32728250. Chromatin immunoprecipitation of the cleaved N-terminal fragment showed it binding oligodendrocyte and myelin gene enhancers through a defined consensus 23966833, which is consistent with this palindrome. Information is concentrated in the TGGT/ACCA core; there are no established spacing rules, and because the site is symmetric, orientation cannot be called from sequence. The family is not fully coherent here (cohesion 0.73, three motifs). The one discordant model is HOCOMOCO's MYRFL entry, a long grade-A model with ChIP-seq, HT-SELEX and GHT-SELEX support (GTGCCAGGCNGTGACATCCC) whose best similarity to any other member of the family is only 0.47, so MYRF and MYRFL should not be assumed to share a site on the current evidence. The yeast middle sporulation element that Ndt80 reads is a different sequence again, with a GC-rich 5' half whose pyrimidine-guanine steps are recognized by arginine side chains through a combination of hydrogen bonding and stacking, and an AT-rich 3' half read through the minor groove 12411490,16531239; it is useful as structural background but not as a human motif.
Where it acts
MYRF sites are found at promoters and, more characteristically, at oligodendrocyte-specific distal enhancers of myelin genes, including MBP, PLP1, MAG and CNP 23966833. Enhancer mapping at the Plp1 locus identified two oligodendrocyte-specific enhancers, both acted on by MYRF, whose contacts with the gene are among the strongest in that cell type 34230963. MYRF works with SOX10 at many of these elements, so a MYRF match near a SOX10 dimer site in oligodendrocyte-accessible chromatin is a much stronger signal than the match alone. As an eight-base fixed palindrome, TGGTACCA is expected by chance on the order of tens of thousands of times in a human genome, most of them in closed chromatin and in cell types where MYRF is absent.
Biology and disease
Mice lacking Myrf in the oligodendrocyte lineage fail to myelinate the central nervous system 19596243, and inducible deletion in adults causes loss of myelin and of mature oligodendrocyte identity 22956843, so MYRF is required for maintenance as well as for differentiation. In humans, de novo MYRF variants cause a syndrome of congenital cardiac and urogenital anomalies, often with congenital diaphragmatic hernia 29446546, and MYRF haploinsufficiency has been reported in both 46,XY and 46,XX disorders of sex development 30985895. The link between a myelin regulator and cardiac and gonadal development is not explained by the oligodendrocyte role, and likely reflects earlier developmental expression.
Reading a hit
The palindrome is short and fully specified, so chance matches are common and the sequence alone carries no cell-type information. A MYRF match matters only in a cell that expresses MYRF, which in practice means the oligodendrocyte lineage; elsewhere the same eight bases are inert. Do not assume that a match to the MYRFL model is equivalent to a MYRF site: that model is discordant with the MYRF palindrome in these data. Because MYRF requires autoproteolytic release to reach the nucleus, the presence of MYRF protein in a tissue does not establish that its DNA-binding fragment is present, which is an unusual extra step between motif and function. Treat the yeast Ndt80 MSE as a separate element that shares only the fold.
How this was worked out
Ndt80 acts at pachytene of yeast meiosis to activate middle sporulation genes, including the B-type cyclins, and recombinant Ndt80 binds a conserved sequence upstream of them, the middle sporulation element (MSE).
Still open then: The structural basis of MSE recognition, and whether the fold had relatives outside fungi.
Crystal structure of the Ndt80 DNA-binding domain, free and on an MSE: an immunoglobulin-like fold whose arginines read 5'-pyrimidine-guanine steps by hydrogen bonding to the guanine and stacking on the pyrimidine; functional parallels suggest a link to the p53 family.
Structures of Ndt80 on ten MSE variants explain its specificity: YpG steps in the GC-rich 5' end read by arginines, and an AT-rich 3' end read through the minor groove with a preference for poly(A)-poly(T) tracts.
Myelin gene regulatory factor (MRF, now MYRF), a protein with a DNA-binding domain homologous to a yeast transcription factor, is expressed by postmitotic oligodendrocytes and required for CNS myelin gene expression and myelination.
Still open then: Whether MYRF binds DNA directly; reports of a transmembrane domain and lack of nuclear localization argued against it.
Deleting MYRF from mature oligodendrocytes in the adult causes delayed but severe demyelination and loss of mature oligodendrocyte identity, so MYRF is needed to maintain myelin, not only to make it.
Two independent groups show MYRF is a membrane-bound precursor that trimerizes and cleaves itself through a domain related to bacteriophage tailspike chaperones; the released N-terminal fragment enters the nucleus and, by ChIP-seq, binds oligodendrocyte and myelin gene enhancers through a defined consensus. This settled the earlier doubt about whether MYRF is a transcription factor at all.
Exome studies tie de novo MYRF variants to a syndrome of cardiac and urogenital anomalies and to 46,XY and 46,XX disorders of sex development, implicating MYRF well outside the CNS.
Still open then: Which MYRF targets act in the affected non-neural tissues.
Still unresolved
- Whether MYRF and MYRFL share a binding site is unresolved: the MYRF models converge on the palindrome TGGTACCA, whereas the only MYRFL model, a grade-A HOCOMOCO model supported by ChIP-seq, HT-SELEX and GHT-SELEX, is a long unrelated sequence (GTGCCAGGCNGTGACATCCC).
- How a trimerizing protein reads a two-fold palindrome is not explained: MYRF trimerizes through its chaperone domain before cleavage, but TGGTACCA has the symmetry expected of a dimeric binder, and the references here do not establish the stoichiometry of the released DNA-binding fragment on DNA.
- Whether MYRF uses the same sites and targets outside the CNS is open: de novo variants cause cardiac, urogenital and gonadal anomalies, but target predictions for those tissues rest on reanalysed ChIP-seq from other cells rather than binding data from the affected tissues.
Only three motifs and two proteins sit under this key, and one of them disagrees with the other two: the HOCOMOCO MYRFL model matches the MYRF palindrome at only 0.47, so MYRF and MYRFL cannot be assumed interchangeable. TGGTACCA is eight fixed bases and a perfect palindrome, so chance matches number in the tens of thousands per genome and orientation is undefined. The site is only interpretable in cells expressing MYRF, essentially the oligodendrocyte lineage. MYRF also needs autoproteolytic cleavage before its DNA-binding fragment reaches the nucleus, so protein presence does not imply DNA binding. The yeast Ndt80 MSE shares the fold but not the sequence.
References
- Chu S, Herskowitz I. Gametogenesis in yeast is regulated by a transcriptional cascade dependent on Ndt80. Mol Cell 1998;1:685-96. PMID 9660952
- Lamoureux JS, Stuart D, Tsang R, et al. Structure of the sporulation-specific transcription factor Ndt80 bound to DNA. EMBO J 2002;21:5721-32. PMID 12411490
- Lamoureux JS, Glover JN. Principles of protein-DNA recognition revealed in the structural analysis of Ndt80-MSE DNA complexes. Structure 2006;14:555-65. PMID 16531239
- Emery B, Agalliu D, Cahoy JD, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell 2009;138:172-85. PMID 19596243
- Bujalka H, Koenning M, Jackson S, et al. MYRF is a membrane-associated transcription factor that autoproteolytically cleaves to directly activate myelin genes. PLoS Biol 2013;11:e1001625. PMID 23966833
- Li Z, Park Y, Marcotte EM. A Bacteriophage tailspike domain promotes self-cleavage of a human membrane-bound transcription factor, the myelin regulatory factor MYRF. PLoS Biol 2013;11:e1001624. PMID 23966832
- Koenning M, Jackson S, Hay CM, et al. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci 2012;32:12528-42. PMID 22956843
- Kim D, An H, Fan C, et al. Identifying oligodendrocyte enhancers governing Plp1 expression. Hum Mol Genet 2021;30:2225-2239. PMID 34230963
- Pinz H, Pyle LC, Li D, et al. De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies. Am J Med Genet A 2018;176:969-972. PMID 29446546
- Hamanaka K, Takata A, Uchiyama Y, et al. MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration. Hum Mol Genet 2019;28:2319-2329. PMID 30985895
- 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
3 motifs in this family — HOCOMOCO 1 · CIS-BP 1 · Vierstra 1
| motif | database | consensus | bits |
|---|---|---|---|
| MRFL.H14CORE.0.PSG.APSGA | HOCOMOCO | GTGCCAggCdGtGaCatcccC | 14.9 |
| M02385_2.00 | CIS-BP | TGGTACCA | 14.1 |
| AC0396:MYRF:Ndt80/PhoG | Vierstra | TGGTACCA | 14.1 |
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.