A unique role of cohesin-SA1 in gene regulation and development

Remeseiro, Silvia; Cuadrado, Ana; Gómez‐López, Gonzalo; Pisano, David G.; Losada, Ana

doi:10.1038/emboj.2012.60

Cited by 135 publications

(174 citation statements)

References 71 publications

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“…Knockout of SA1 in mouse resulted in embryonic lethality (Remeseiro et al, 2012a;Remeseiro et al, 2012b). While analysis of SA1-null mouse cells indicated defects in telomere cohesion and telomere replication (Remeseiro et al, 2012a) [consistent with studies in human cells (Canudas and Smith, 2009)], additional observations indicated a role for SA1 in different processes.…”

Section: Discussionmentioning

confidence: 65%

“…While analysis of SA1-null mouse cells indicated defects in telomere cohesion and telomere replication (Remeseiro et al, 2012a) [consistent with studies in human cells (Canudas and Smith, 2009)], additional observations indicated a role for SA1 in different processes. Analysis of the distribution of SA1-cohesin versus SA2-cohesin in the non-repetitive parts of the mouse genome by ChIP-sequencing indicated striking differences in their genomic distribution; SA1 was enriched at promoters and SA1 null cells showed dramatic changes in gene expression (Remeseiro et al, 2012b). Considering that AT-hook containing proteins have been shown to function in chromatin remodeling and transcription, it is tempting to speculate that SA1 may directly impact transcription through its unique AT-hook.…”

Section: Discussionmentioning

confidence: 99%

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SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Bisht

Daniloski

Smith

2013

Journal of Cell Science

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SummarySister chromatid cohesion relies on cohesin, a complex comprising a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) N-terminal domain, which we show binds to telomeric DNA through an AT-hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Bisht

Daniloski

Smith

2013

Journal of Cell Science

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“…For example, cohesin-mediated DNA looping may be required only at the time of alternative promoter choice, whereas a cohesin-independent activity of CTCF, such as blocking the spread of heterochromatin (26), may be required for the maintenance of choice. In any case, we note that after this manuscript was submitted for publication, the cohesin subunit SA1, which is responsible for cohesin accumulation at promoters bound by CTCF, was shown to be required for normal Pcdh gene expression in mice (27).…”

Section: Discussionmentioning

confidence: 99%

Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression

Monahan

Rudnick

Kehayova

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

126

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Extraordinary single-cell diversity is generated in the vertebrate nervous system by the combinatorial expression of the clustered protocadherin genes (Pcdhα, -β, and -γ). This diversity is generated by a combination of stochastic promoter choice and alternative premRNA splicing. Here we show that both the insulator-binding protein CTCF and the cohesin complex subunit Rad21 bind to two highly conserved DNA sequences, the first within and the second downstream of transcriptionally active Pcdhα promoters. Both CTCF and Rad21 bind to these sites in vitro and in vivo, this binding directly correlates with alternative isoform expression, and knocking down CTCF expression reduces alternative isoform expression. Remarkably, a similarly spaced pair of CTCF/Rad21 binding sites was identified within a distant enhancer element (HS5-1), which is required for normal levels of alternative isoform expression. We also identify an additional, unique regulatory role for cohesin, as Rad21 binds to another enhancer (HS7) independently of CTCF, and knockdown of Rad21 reduces expression of the constitutive, biallelically expressed Pcdhα isoforms αc1 and αc2. We propose that CTCF and the cohesin complex initiate and maintain Pcdhα promoter choice by mediating interactions between Pcdhα promoters and enhancers.

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“…In line with this, mouse embryonic fibroblasts lacking SA1 show a dramatic change in the distribution of cohesin, which shows reduced presence at promoters and CTCF sites. As a consequence, gene expression is altered in a way that affects embryonic development in SA1-null mice (Remeseiro et al, 2012b).…”

Section: Cohesin and Transcriptionmentioning

confidence: 99%

Cohesin in development and disease

2013

Self Cite

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SummaryCohesin is a ring-shaped complex, conserved from yeast to human, that was named for its ability to mediate sister chromatid cohesion. This function is essential for chromosome segregation in both mitosis and meiosis, and also for DNA repair. In addition, more recent studies have shown that cohesin influences gene expression during development through mechanisms that likely involve DNA looping and interactions with several transcriptional regulators. Here, we provide an overview of how cohesin functions, highlighting its role both in development and in disease. Key words: Chromatin loops, Cohesion, Cohesinopathies IntroductionThe development of a complex multicellular organism from the fusion of two haploid cells requires two fundamental processes:one is cell proliferation, in order to grow; the other is cell differentiation, in order to generate specialized cells for tissues and organs. The cohesin complex plays key roles in both these processes. Cohesin was originally identified as the mediator of sister chromatid cohesion. It establishes a physical link between the two sister chromatids from the moment they arise from the replication fork. This link is essential for efficient DNA repair by homologous recombination during S/G2, and for proper chromosome alignment and segregation in mitosis. In this way, cohesin ensures the accurate transmission of genetic material during cell proliferation. Regarding cell differentiation, it is clear that what defines a cell type is not its genome, but how this genome is used. Increasing evidence supports the importance of higher order chromatin structure in the temporal and spatial regulation of transcription. We are only beginning to understand how the spatial organization of chromatin affects gene expression, but cohesin is emerging as an important contributor to such organization. Here, and in the accompanying poster, we briefly review our current knowledge of cohesin and its different functions, and focus on how these functions contribute to embryonic development. Development 140, 3715-3718 (2013) DEVELOPMENT 3716The cohesin complex Cohesin consists of four subunits -Smc1, Smc3, Scc1/Rad21 and Scc3/SA -arranged in a ring-shaped structure. Smc1 and Smc3 belong to the structural maintenance of chromosomes (SMC) family of chromosomal ATPases that also includes the core subunits of condensin and of the Smc5/6 complex. These complexes are conserved from yeast to human, and SMC-like proteins contribute to chromosome organization and dynamics in bacteria and archaea (Hirano, 2005). Scc1/Rad21 belongs to the kleisin protein family and interacts with both Smc1 and Smc3 to close the ring. The Scc3/SA subunit in somatic vertebrate cells can be either SA1 or SA2, although additional variants for SA and other subunits also exist in meiotic cells.The regulation of cohesin during the cell cycle Cohesin topologically embraces chromatin fiber(s) within its ringshaped structure (Nasmyth, 2011). The complex is recruited to chromatin during G1 in a process that requires the cohesini...

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A unique role of cohesin-SA1 in gene regulation and development

Cited by 135 publications

References 71 publications

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

SA1 binds directly to DNA via its unique AT-hook to promote sister chromatid cohesion at telomeres

Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression

Cohesin in development and disease

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