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The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development
X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD Finger 8) is...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072215/ https://www.ncbi.nlm.nih.gov/pubmed/20622853 http://dx.doi.org/10.1038/nature09261 |
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author | Qi, Hank H. Sarkissian, Madathia Hu, Gang-Qing Wang, Zhibin Bhattacharjee, Arindam Gordon, D. Benjamin Gonzales, Michelle Lan, Fei Ongusaha, Pat P. Huarte, Maite Yaghi, Nasser K. Lim, Huijun Garcia, Benjamin A. Brizuela, Leonardo Zhao, Keji Roberts, Thomas M. Shi, Yang |
author_facet | Qi, Hank H. Sarkissian, Madathia Hu, Gang-Qing Wang, Zhibin Bhattacharjee, Arindam Gordon, D. Benjamin Gonzales, Michelle Lan, Fei Ongusaha, Pat P. Huarte, Maite Yaghi, Nasser K. Lim, Huijun Garcia, Benjamin A. Brizuela, Leonardo Zhao, Keji Roberts, Thomas M. Shi, Yang |
author_sort | Qi, Hank H. |
collection | PubMed |
description | X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD Finger 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 up-regulation 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 developing 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 signaling and developmental pathways3. Our findings suggest that an imbalance of histone methylation dynamics plays a critical role in XLMR. |
format | Text |
id | pubmed-3072215 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
record_format | MEDLINE/PubMed |
spelling | pubmed-30722152011-04-07 The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development Qi, Hank H. Sarkissian, Madathia Hu, Gang-Qing Wang, Zhibin Bhattacharjee, Arindam Gordon, D. Benjamin Gonzales, Michelle Lan, Fei Ongusaha, Pat P. Huarte, Maite Yaghi, Nasser K. Lim, Huijun Garcia, Benjamin A. Brizuela, Leonardo Zhao, Keji Roberts, Thomas M. Shi, Yang Nature Article X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability1. Causal mutations have been found in approximately 90 X-linked genes2; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD Finger 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 up-regulation 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 developing 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 signaling and developmental pathways3. Our findings suggest that an imbalance of histone methylation dynamics plays a critical role in XLMR. 2010-07-11 2010-07-22 /pmc/articles/PMC3072215/ /pubmed/20622853 http://dx.doi.org/10.1038/nature09261 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Qi, Hank H. Sarkissian, Madathia Hu, Gang-Qing Wang, Zhibin Bhattacharjee, Arindam Gordon, D. Benjamin Gonzales, Michelle Lan, Fei Ongusaha, Pat P. Huarte, Maite Yaghi, Nasser K. Lim, Huijun Garcia, Benjamin A. Brizuela, Leonardo Zhao, Keji Roberts, Thomas M. Shi, Yang The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title | The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title_full | The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title_fullStr | The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title_full_unstemmed | The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title_short | The XLMR gene PHF8 encodes a histone H4K20/H3K9 demethylase and regulates zebrafish brain and craniofacial development |
title_sort | xlmr gene phf8 encodes a histone h4k20/h3k9 demethylase and regulates zebrafish brain and craniofacial development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072215/ https://www.ncbi.nlm.nih.gov/pubmed/20622853 http://dx.doi.org/10.1038/nature09261 |
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