Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells

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Abstract

Loss of the condensin complex components Smc2 and -4 disrupts epigenetic modifications required for embryonic stem cell survival.

Abstract

In an RNA interference screen interrogating regulators of mouse embryonic stem (ES) cell chromatin structure, we previously identified 62 genes required for ES cell viability. Among these 62 genes were Smc2 and - 4, which are core components of the two mammalian condensin complexes. In this study, we show that for Smc2 and - 4, as well as an additional 49 of the 62 genes, knockdown (KD) in somatic cells had minimal effects on proliferation or viability. Upon KD, Smc2 and - 4 exhibited two phenotypes that were unique to ES cells and unique among the ES cell–lethal targets: metaphase arrest and greatly enlarged interphase nuclei. Nuclear enlargement in condensin KD ES cells was caused by a defect in chromatin compaction rather than changes in DNA content. The altered compaction coincided with alterations in the abundance of several epigenetic modifications. These data reveal a unique role for condensin complexes in interphase chromatin compaction in ES cells.

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Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

G Martin (1981)

This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.

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Establishment in culture of pluripotential cells from mouse embryos.

Sydney M. Evans, H Kaufman (1981)

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A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.

T T Paull, E P Rogakou, V Yamazaki … (2000)

The response of eukaryotic cells to double-strand breaks in genomic DNA includes the sequestration of many factors into nuclear foci. Recently it has been reported that a member of the histone H2A family, H2AX, becomes extensively phosphorylated within 1-3 minutes of DNA damage and forms foci at break sites. In this work, we examine the role of H2AX phosphorylation in focus formation by several repair-related complexes, and investigate what factors may be involved in initiating this response. Using two different methods to create DNA double-strand breaks in human cells, we found that the repair factors Rad50 and Rad51 each colocalized with phosphorylated H2AX (gamma-H2AX) foci after DNA damage. The product of the tumor suppressor gene BRCA1 also colocalized with gamma-H2AX and was recruited to these sites before Rad50 or Rad51. Exposure of cells to the fungal inhibitor wortmannin eliminated focus formation by all repair factors examined, suggesting a role for the phosphoinositide (PI)-3 family of protein kinases in mediating this response. Wortmannin treatment was effective only when it was added early enough to prevent gamma-H2AX formation, indicating that gamma-H2AX is necessary for the recruitment of other factors to the sites of DNA damage. DNA repair-deficient cells exhibit a substantially reduced ability to increase the phosphorylation of H2AX in response to ionizing radiation, consistent with a role for gamma-H2AX in DNA repair. The pattern of gamma-H2AX foci that is established within a few minutes of DNA damage accounts for the patterns of Rad50, Rad51, and Brca1 foci seen much later during recovery from damage. The evidence presented strongly supports a role for the gamma-H2AX and the PI-3 protein kinase family in focus formation at sites of double-strand breaks and suggests the possibility of a change in chromatin structure accompanying double-strand break repair.

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Author and article information

Journal

Journal ID (nlm-ta): J Cell Biol

Journal ID (iso-abbrev): J. Cell Biol

Journal ID (hwp): jcb

Title: The Journal of Cell Biology

Publisher: The Rockefeller University Press

ISSN (Print): 0021-9525

ISSN (Electronic): 1540-8140

Publication date (Print): 22 February 2010

Volume: 188

Issue: 4

Pages: 491-503

Affiliations

Biochemistry and Biophysics Department, University of California, San Francisco, San Francisco, CA 94158

Author notes

Correspondence to Thomas G. Fazzio: thomas.fazzio@ 123456ucsf.edu ; or Barbara Panning: barbara.panning@ 123456ucsf.edu

Article

Publisher ID: 200908026

DOI: 10.1083/jcb.200908026

PMC ID: 2828918

PubMed ID: 20176923

SO-VID: c52d622f-483e-427d-a418-c88be132af68

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells

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Stress signalling in stem cells

Most cited references 47

Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

Establishment in culture of pluripotential cells from mouse embryos.

A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage.

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