TY - JOUR
T1 - Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development
AU - Qi, Hank H.
AU - Sarkissian, Madathia
AU - Hu, Gang Qing
AU - Wang, Zhibin
AU - Bhattacharjee, Arindam
AU - Gordon, D. Benjamin
AU - Gonzales, Michelle
AU - Lan, Fei
AU - Ongusaha, Pat P.
AU - Huarte, Maite
AU - Yaghi, Nasser K.
AU - Lim, Huijun
AU - Garcia, Benjamin A.
AU - Brizuela, Leonardo
AU - Zhao, Keji
AU - Roberts, Thomas M.
AU - Shi, Yang
N1 - Funding Information:
Acknowledgements We thank Shi laboratory members for helpful discussions and N. Mosammaparast and S. Chen for providing the nucleosomes. We thank G. Rosenfeld for sharing unpublished PHF8 results, and G. Rosenfeld, A. Schier and P. Hinds for discussions. H.H.Q. is a recipient of Ruth L. Kirschstein-National Service Research Award (T32 NS007473 and T32 CA09031-32). N.K.Y. was supported by Harvard SHURP (Summer Honors Undergraduate Research Program). H.L. is a recipient of the Agency for Science, Technology and Research (A*STAR) National Science Scholarship. This work was supported by grants from the National Science Foundation (CBET-0941143) to B.A.G.; NIH (GM 071004 and NCI118487) to Y.S.; a Senior Scholar Grant from the Ellison Foundation, and an NIH PO1 grant (CA50661) to T.M.R.
PY - 2010/7/23
Y1 - 2010/7/23
N2 - X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of ∼7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
AB - X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of ∼7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
UR - http://www.scopus.com/inward/record.url?scp=77954957901&partnerID=8YFLogxK
U2 - 10.1038/nature09261
DO - 10.1038/nature09261
M3 - Article
C2 - 20622853
AN - SCOPUS:77954957901
SN - 0028-0836
VL - 466
SP - 503
EP - 507
JO - Nature
JF - Nature
IS - 7305
ER -