Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells

Bo Wen; Hao Wu; Yoichi Shinkai; Rafael A. Irizarry; Andrew P. Feinberg

doi:10.1038/ng.297

Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells

Bo Wen, Hao Wu, Yoichi Shinkai, Rafael A. Irizarry, Andrew P. Feinberg

School of Medicine

Research output: Contribution to journal › Article › peer-review

415 Scopus citations

Abstract

Higher eukaryotes must adapt a totipotent genome to specialized cell types with stable but limited functions. One potential mechanism for lineage restriction is changes in chromatin, and differentiation-related chromatin changes have been observed for individual genes. We have taken a genome-wide view of histone H3 lysine 9 dimethylation (H3K9Me2) and find that differentiated tissues show surprisingly large K9-modified regions (up to 4.9 Mb). These regions are highly conserved between human and mouse and are differentiation specific, covering only ∼4% of the genome in undifferentiated mouse embryonic stem (ES) cells, compared to 31% in differentiated ES cells, ∼46% in liver and ∼10% in brain. These modifications require histone methyltransferase G9a and are inversely related to expression of genes within the regions. We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type-heritable mechanism for phenotypic plasticity in development and disease.

Original language	English (US)
Pages (from-to)	246-250
Number of pages	5
Journal	Nature genetics
Volume	41
Issue number	2
DOIs	https://doi.org/10.1038/ng.297
State	Published - Feb 2009

ASJC Scopus subject areas

Genetics

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title = "Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells",

abstract = "Higher eukaryotes must adapt a totipotent genome to specialized cell types with stable but limited functions. One potential mechanism for lineage restriction is changes in chromatin, and differentiation-related chromatin changes have been observed for individual genes. We have taken a genome-wide view of histone H3 lysine 9 dimethylation (H3K9Me2) and find that differentiated tissues show surprisingly large K9-modified regions (up to 4.9 Mb). These regions are highly conserved between human and mouse and are differentiation specific, covering only ∼4% of the genome in undifferentiated mouse embryonic stem (ES) cells, compared to 31% in differentiated ES cells, ∼46% in liver and ∼10% in brain. These modifications require histone methyltransferase G9a and are inversely related to expression of genes within the regions. We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type-heritable mechanism for phenotypic plasticity in development and disease.",

author = "Bo Wen and Hao Wu and Yoichi Shinkai and Irizarry, {Rafael A.} and Feinberg, {Andrew P.}",

note = "Funding Information: We thank S. Taverna, K. Reddy, R. Ohlsson and C. Sapienza for helpful discussions, and S. Taverna and W. Timp for assistance with illustration. This work was supported by US National Institutes of Health grant P50HG003233 to A.P.F.",

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doi = "10.1038/ng.297",

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AU - Wen, Bo

AU - Wu, Hao

AU - Shinkai, Yoichi

AU - Irizarry, Rafael A.

AU - Feinberg, Andrew P.

N1 - Funding Information: We thank S. Taverna, K. Reddy, R. Ohlsson and C. Sapienza for helpful discussions, and S. Taverna and W. Timp for assistance with illustration. This work was supported by US National Institutes of Health grant P50HG003233 to A.P.F.

PY - 2009/2

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N2 - Higher eukaryotes must adapt a totipotent genome to specialized cell types with stable but limited functions. One potential mechanism for lineage restriction is changes in chromatin, and differentiation-related chromatin changes have been observed for individual genes. We have taken a genome-wide view of histone H3 lysine 9 dimethylation (H3K9Me2) and find that differentiated tissues show surprisingly large K9-modified regions (up to 4.9 Mb). These regions are highly conserved between human and mouse and are differentiation specific, covering only ∼4% of the genome in undifferentiated mouse embryonic stem (ES) cells, compared to 31% in differentiated ES cells, ∼46% in liver and ∼10% in brain. These modifications require histone methyltransferase G9a and are inversely related to expression of genes within the regions. We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type-heritable mechanism for phenotypic plasticity in development and disease.

AB - Higher eukaryotes must adapt a totipotent genome to specialized cell types with stable but limited functions. One potential mechanism for lineage restriction is changes in chromatin, and differentiation-related chromatin changes have been observed for individual genes. We have taken a genome-wide view of histone H3 lysine 9 dimethylation (H3K9Me2) and find that differentiated tissues show surprisingly large K9-modified regions (up to 4.9 Mb). These regions are highly conserved between human and mouse and are differentiation specific, covering only ∼4% of the genome in undifferentiated mouse embryonic stem (ES) cells, compared to 31% in differentiated ES cells, ∼46% in liver and ∼10% in brain. These modifications require histone methyltransferase G9a and are inversely related to expression of genes within the regions. We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type-heritable mechanism for phenotypic plasticity in development and disease.

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Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells

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