LSH mediates gene repression through macroH2A deposition
| Autor: | Nathaniel A. Hathaway, Yafeng He, Gerald R. Crabtree, Kathrin Muegge, Simon M. G. Braun, Richard Finney, Jianke Ren, Kai Ni, Xiaoping Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Transcription Genetic Primary Immunodeficiency Diseases Science Regulator General Physics and Astronomy Down-Regulation Chromatin remodelling General Biochemistry Genetics and Molecular Biology Chromatin remodeling Article Histones 03 medical and health sciences Mice 0302 clinical medicine Genetic Transcription (biology) DNA Helicases/genetics/metabolism parasitic diseases Gene silencing Animals Humans lcsh:Science Gene Histones/genetics/metabolism Primary Immunodeficiency Diseases/enzymology/genetics/metabolism Regulation of gene expression Chromatin/genetics/metabolism Multidisciplinary biology Disease genetics DNA Helicases General Chemistry Chromatin Cell biology Gene regulation 030104 developmental biology Histone Mechanisms of disease biology.protein Female lcsh:Q Transcription 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) Nature Communications Nature Communications, Vol. 11, No 1 (2020) P. 5647 |
| ISSN: | 2041-1723 |
| DOI: | 10.17615/062g-y155 |
| Popis: | The human Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is a severe disease with increased mortality caused by mutation in the LSH gene. Although LSH belongs to a family of chromatin remodeling proteins, it remains unknown how LSH mediates its function on chromatin in vivo. Here, we use chemical-induced proximity to rapidly recruit LSH to an engineered locus and find that LSH specifically induces macroH2A1.2 and macroH2A2 deposition in an ATP-dependent manner. Tethering of LSH induces transcriptional repression and silencing is dependent on macroH2A deposition. Loss of LSH decreases macroH2A enrichment at repeat sequences and results in transcriptional reactivation. Likewise, reduction of macroH2A by siRNA interference mimicks transcriptional reactivation. ChIP-seq analysis confirmed that LSH is a major regulator of genome-wide macroH2A distribution. Tethering of ICF4 mutations fails to induce macroH2A deposition and ICF4 patient cells display reduced macroH2A deposition and transcriptional reactivation supporting a pathogenic role for altered marcoH2A deposition. We propose that LSH is a major chromatin modulator of the histone variant macroH2A and that its ability to insert marcoH2A into chromatin and transcriptionally silence is disturbed in the ICF4 syndrome. The human ICF 4 syndrome is caused by mutation of the chromatin remodeller LSH. Here, the authors show that LSH depletion disrupts the ability of histone variant macroH2A to insert into chromatin and silence transcription. |
| Databáze: | OpenAIRE |
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