RFX4 explained

Transcription factor RFX4 is a protein that in humans is encoded by the RFX4 gene.^{[1] [2] [3]}

This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X3, and X5. It has been shown to interact with itself as well as with regulatory factors X2 and X3, but it does not interact with regulatory factor X1. This protein may be a transcriptional repressor rather than a transcriptional activator. Three transcript variants encoding different isoforms have been described for this gene.

RFX4 has been implicated in neural-lineage specification and in glioblastoma cell-state control: pooled transcription-factor overexpression with single-cell RNA-seq identified RFX4 as sufficient to induce neural progenitor–like programs from human pluripotent stem cells that differentiate toward CNS neuron and glia lineages,^[4] and in glioblastoma, RFX4 was reported as an orchestrator of growth and differentiation in diffusely invading tumor cells, where perturbation redistributed invasion routes and extended survival in xenografts.^[5]

Further reading

• Dotzlaw H, Alkhalaf M, Murphy LC . 1992 . Characterization of estrogen receptor variant mRNAs from human breast cancers . Mol. Endocrinol. . 6 . 5 . 773–85 . 10.1210/mend.6.5.1603086 . 1603086 . 25208340 . free.
• Reith W . Ucla C . Barras E . Gaud . A . Durand . B . Herrero-Sanchez . C . Kobr . M . Mach . B . 1994 . RFX1, a transactivator of hepatitis B virus enhancer I, belongs to a novel family of homodimeric and heterodimeric DNA-binding proteins . Mol. Cell. Biol. . 14 . 2 . 1230–44 . 10.1128/mcb.14.2.1230 . 358479 . 8289803.
• Gajiwala KS . Chen H . Cornille F . Roques . Bernard P. . Reith . Walter . Mach . Bernard . Burley . Stephen K. . 2000 . Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding . Nature . 403 . 6772 . 916–21 . 2000Natur.403..916G . 10.1038/35002634 . 10706293 . 4425783.
• Strausberg RL . Feingold EA . Grouse LH . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2003 . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2002PNAS...9916899M . 10.1073/pnas.242603899 . 139241 . 12477932 . free.
• Blackshear PJ . Graves JP . Stumpo DJ . Cobos . I . Rubenstein . JL . Zeldin . DC . 2003 . Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4 . Development . 130 . 19 . 4539–52 . 10.1242/dev.00661 . 12925582 . free.
• Araki R . Takahashi H . Fukumura R . Sun . F . Umeda . N . Sujino . M . Inouye . ST . Saito . T . Abe . M . 2004 . Restricted expression and photic induction of a novel mouse regulatory factor X4 transcript in the suprachiasmatic nucleus . J. Biol. Chem. . 279 . 11 . 10237–42 . 10.1074/jbc.M312761200 . 14701801 . free.
• Glaser B . Kirov G . Bray NJ . Green . E . O'Donovan . M C . Craddock . N . Owen . M J . 2005 . Identification of a potential bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4 . Mol. Psychiatry . 10 . 10 . 920–7 . 10.1038/sj.mp.4001689 . 15940297 . free.
• Rual JF . Venkatesan K . Hao T . Hirozane-Kishikawa . Tomoko . Dricot . Amélie . Li . Ning . Berriz . Gabriel F. . Gibbons . Francis D. . Dreze . Matija. 2005 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . 2005Natur.437.1173R . 10.1038/nature04209 . 16189514 . 4427026.
• Matsushita H . Uenaka A . Ono T . Hasegawa . Kosei . Sato . Shuichiro . Koizumi . Fumihito . Nakagawa . Kazuhiko . Toda . Masahiro . Shingo . Tetsuro . 2006 . Identification of glioma-specific RFX4-E and -F isoforms and humoral immune response in patients . Cancer Sci. . 96 . 11 . 801–9 . 10.1111/j.1349-7006.2005.00112.x . 11159248 . 16271074 . 25967004.

Notes and References

1. Emery P, Durand B, Mach B, Reith W . May 1996 . RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom . Nucleic Acids Res . 24 . 5 . 803–7 . 10.1093/nar/24.5.803 . 145730 . 8600444.
2. Morotomi-Yano K, Yano K, Saito H, Sun Z, Iwama A, Miki Y . Jan 2002 . Human regulatory factor X 4 (RFX4) is a testis-specific dimeric DNA-binding protein that cooperates with other human RFX members . J Biol Chem . 277 . 1 . 836–42 . 10.1074/jbc.M108638200 . 11682486 . free.
3. Web site: Entrez Gene: RFX4 regulatory factor X, 4 (influences HLA class II expression) .
4. Joung J, Ma S, Tay T, Geiger-Schuller KR, Kirchgatterer PC, Verdine VK, Guo B, Arias-Garcia MA, Allen WE, Singh A, Kuksenko O, Abudayyeh OO, Gootenberg JS, Fu Z, Macrae RK, Buenrostro JD, Regev A, Zhang F . January 5, 2023 . A transcription factor atlas of directed differentiation . Cell . 186 . 1 . 209–229.e26 . 10.1016/j.cell.2022.11.026 . 10344468 . 36608654.
5. Doroszko M, Stockgard R, Uppman I, Heinold J, Voukelatou F, Mangukiya HB, Millner TO, Skeppås M, Ballester Bravo M, Elgendy R, Berglund M, Elfineh L, Krona C, Kundu S, Koltowska K, Marino S, Larsson I, Nelander S . July 19, 2025 . The invasion phenotypes of glioblastoma depend on plastic and reprogrammable cell states . Nature Communications . 16 . 1 . 6662 . 10.1038/s41467-025-61999-1 . 12276355 . 40683881 . 2025NatCo..16.6662D .