Brpf1 Explained

Peregrin also known as bromodomain and PHD finger-containing protein 1 is a protein that in humans is encoded by the BRPF1 gene located on 3p26-p25. Peregrin is a multivalent chromatin regulator that recognizes different epigenetic marks and activates three histone acetyltransferases (Moz, Morf and Hbo1). BRPF1 contains two PHD fingers, one bromodomain and one chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.

Function

Embryo development

Brpf1 gene is very conserved and has a critical role in different developmental processes.^{[1] [2] [3]} Zebrafish BRPF1, which is coordinated by its particular set of PWWP domains, mediates Moz -dependent histone acetylation and maintains Hox genes expression throughout vertebrate development, hence determines the proper pharyngeal segmental identities.^[4] Furthermore, Brpf1 may not only has significant role for maintaining the anterior-posterior axis of the craniofacial skeleton, but also the dorsal-ventral axis of the caudal skeleton.^[5] Recent studies have shown that ablation of the mouse Brpf1 gene causes embryonic lethality at embryonic day 9.5. Specifically, Brpf1 regulates placenta vascular formation, neural tube closure, primitive hematopoiesis and embryonic fibroblast proliferation.

For the central nervous system, Brpf1 has high expression and is essential for the development of several important structures, including neocortex and dentate gyrus in the hippocampus. Brpf1 is dynamically expressed during forebrain development, especially the hippocampal neurogenesis.^[6] Brpf1 shares phenotypes with transcription factors Sox2, Tlx and Tbr2 in dentate gyrus development and has potential link to neural stem cells and progenitors. Except for the forebrain, Brpf1 is also required for the proper patterning of the craniofacial cartilage, which is derived from neural crest cells that migrate from the hindbrain.^[7]

Cancer development

Recently, Brpf1 was reported to play the tumor suppressor or oncogenic role in several malignant tumors, including leukemia, medulloblastoma and endometrial stromal sarcoma.^{[8] [9] [10]} Brpf1 was considered a tumor suppressor gene because mutations in cancer cells appear to diminish the function of Brpf1 However, oncogenic role of Brpf1 is also possible in cancer. For example, Brpf1 can form a stable complex with Moz-Tif2, which could lead to the development of human acute myeloid leukemia (AML). There is another Brpf1 related complex Brpf1–Ing5–Eaf6, which also plays a direct role in cancer.

See also

• Pattern formation
• Regional specification

Further reading

• Klein BJ, Muthurajan UM, Lalonde ME, Gibson MD, Andrews FH, Hepler M, Machida S, Yan K, Kurumizaka H, Poirier MG, Côté J, Luger K, Kutateladze TG . Bivalent interaction of the PZP domain of BRPF1 with the nucleosome impacts chromatin dynamics and acetylation . Nucleic Acids Research . 44 . 1 . 472–84 . Jan 2016 . 26626149 . 4705663 . 10.1093/nar/gkv1321 .
• You L, Zou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ . Deficiency of the chromatin regulator BRPF1 causes abnormal brain development . The Journal of Biological Chemistry . 290 . 11 . 7114–29 . Mar 2015 . 25568313 . 4358132 . 10.1074/jbc.M114.635250 . free .
• Lubula MY, Eckenroth BE, Carlson S, Poplawski A, Chruszcz M, Glass KC . Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain . FEBS Letters . 588 . 21 . 3844–54 . Nov 2014 . 25281266 . 4252766 . 10.1016/j.febslet.2014.09.028 .
• Carlson S, Glass KC . The MOZ histone acetyltransferase in epigenetic signaling and disease . Journal of Cellular Physiology . 229 . 11 . 1571–4 . Nov 2014 . 24633655 . 4750494 . 10.1002/jcp.24617 .
• Poplawski A, Hu K, Lee W, Natesan S, Peng D, Carlson S, Shi X, Balaz S, Markley JL, Glass KC . Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain . Journal of Molecular Biology . 426 . 8 . 1661–76 . Apr 2014 . 24333487 . 3969779 . 10.1016/j.jmb.2013.12.007 .
• Qin S, Jin L, Zhang J, Liu L, Ji P, Wu M, Wu J, Shi Y . Recognition of unmodified histone H3 by the first PHD finger of bromodomain-PHD finger protein 2 provides insights into the regulation of histone acetyltransferases monocytic leukemic zinc-finger protein (MOZ) and MOZ-related factor (MORF) . The Journal of Biological Chemistry . 286 . 42 . 36944–55 . Oct 2011 . 21880731 . 3196140 . 10.1074/jbc.M111.244400 . free .
• Mishima Y, Miyagi S, Saraya A, Negishi M, Endoh M, Endo TA, Toyoda T, Shinga J, Katsumoto T, Chiba T, Yamaguchi N, Kitabayashi I, Koseki H, Iwama A . The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis . Blood . 118 . 9 . 2443–53 . Sep 2011 . 21753189 . 10.1182/blood-2011-01-331892 . free .
• Vezzoli A, Bonadies N, Allen MD, Freund SM, Santiveri CM, Kvinlaug BT, Huntly BJ, Göttgens B, Bycroft M . Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1 . Nature Structural & Molecular Biology . 17 . 5 . 617–9 . May 2010 . 20400950 . 10.1038/nsmb.1797 . 38082800 .
• Hibiya K, Katsumoto T, Kondo T, Kitabayashi I, Kudo A . Brpf1, a subunit of the MOZ histone acetyl transferase complex, maintains expression of anterior and posterior Hox genes for proper patterning of craniofacial and caudal skeletons . Developmental Biology . 329 . 2 . 176–90 . May 2009 . 19254709 . 10.1016/j.ydbio.2009.02.021 .
• Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Côté J, Yang XJ . Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes . Molecular and Cellular Biology . 28 . 22 . 6828–43 . Nov 2008 . 18794358 . 2573306 . 10.1128/MCB.01297-08 .
• Poplawski A, Hu K, Lee W, Natesan S, Peng D, Carlson S, Shi X, Balaz S, Markley JL, Glass KC . Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain . Journal of Molecular Biology . 426 . 8 . 1661–76 . Apr 2014 . 24333487 . 3969779 . 10.1016/j.jmb.2013.12.007 .

Notes and References

1. Yang XJ . MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1853 . 8 . 1818–26 . 2015 . 25920810 . 10.1016/j.bbamcr.2015.04.014 . free .
2. You L, Chen L, Penney J, Miao D, Yang XJ . Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos . Epigenetics . 9 . 6 . 860–72 . 2014 . 24646517 . 4065184 . 10.4161/epi.28530 .
3. You L, Yan K, Zou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ . The chromatin regulator Brpf1 regulates embryo development and cell proliferation . The Journal of Biological Chemistry . 290 . 18 . 11349–64 . 2015 . 25773539 . 10.1074/jbc.M115.643189 . 4416840. free .
4. Laue K, Daujat S, Crump JG, Plaster N, Roehl HH, Kimmel CB, Schneider R, Hammerschmidt M . The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity . Development . 135 . 11 . 1935–46 . 2008 . 18469222 . 2919486 . 10.1242/dev.017160 .
5. Hibiya K, Katsumoto T, Kondo T, Kitabayashi I, Kudo A . Brpf1, a subunit of the MOZ histone acetyl transferase complex, maintains expression of anterior and posterior Hox genes for proper patterning of craniofacial and caudal skeletons . Developmental Biology . 329 . 2 . 176–90 . 2009 . 19254709 . 10.1016/j.ydbio.2009.02.021 .
6. You L, Yan K, Zou J, Zhou J, Zhao H, Bertos NR, Park M, Wang E, Yang XJ . The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors . PLOS Genetics . 11 . 3 . e1005034 . 2015 . 25757017 . 4355587 . 10.1371/journal.pgen.1005034 . free .
7. Yan K, You L, Degerny C, Ghorbani M, Liu X, Chen L, Li L, Miao D, Yang XJ . The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival . The Journal of Biological Chemistry . 291 . 6 . 2647–63 . 2016 . 26677226 . 10.1074/jbc.M115.703041 . 4742735 . free .
8. Kool M, Jones DT, Jäger N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, Milde T, Bourdeaut F, Ryzhova M, Sturm D, Pfaff E, Stark S, Hutter S, Seker-Cin H, Johann P, Bender S, Schmidt C, Rausch T, Shih D, Reimand J, Sieber L, Wittmann A, Linke L, Witt H, Weber UD, Zapatka M, König R, Beroukhim R, Bergthold G, van Sluis P, Volckmann R, Koster J, Versteeg R, Schmidt S, Wolf S, Lawerenz C, Bartholomae CC, von Kalle C, Unterberg A, Herold-Mende C, Hofer S, Kulozik AE, von Deimling A, Scheurlen W, Felsberg J, Reifenberger G, Hasselblatt M, Crawford JR, Grant GA, Jabado N, Perry A, Cowdrey C, Croul S, Zadeh G, Korbel JO, Doz F, Delattre O, Bader GD, McCabe MG, Collins VP, Kieran MW, Cho YJ, Pomeroy SL, Witt O, Brors B, Taylor MD, Schüller U, Korshunov A, Eils R, Wechsler-Reya RJ, Lichter P, Pfister SM . 6 . Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition . Cancer Cell . 25 . 3 . 393–405 . 2014 . 24651015 . 4493053 . 10.1016/j.ccr.2014.02.004 .
9. Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, Ma J, Edmonson MN, Hedlund EK, Rusch MC, Shurtleff SA, Mulder HL, Boggs K, Vadordaria B, Cheng J, Yergeau D, Song G, Becksfort J, Lemmon G, Weber C, Cai Z, Dang J, Walsh M, Gedman AL, Faber Z, Easton J, Gruber T, Kriwacki RW, Partridge JF, Ding L, Wilson RK, Mardis ER, Mullighan CG, Gilbertson RJ, Baker SJ, Zambetti G, Ellison DW, Zhang J, Downing JR . 6 . The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes . Nature Communications . 5 . 3630 . 2014 . 24710217 . 4119022 . 10.1038/ncomms4630 . 2014NatCo...5.3630H .
10. Shima H, Yamagata K, Aikawa Y, Shino M, Koseki H, Shimada H, Kitabayashi I . Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ-TIF2 fusion . International Journal of Hematology . 99 . 1 . 21–31 . 2014 . 24258712 . 10.1007/s12185-013-1466-x . 207400403 .