ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

Zhaomin Li; Peng Zhang; Aimin Yan; Zhengyu Guo; Yuguang Ban; Jin Li; Shi Chen; Hui Yang; Yongzheng He; Jianping Li; Ying Guo; Wen Zhang; Ehsan Hajiramezanali; Huangda An; Darlene Fajardo; J. William Harbour; Yijun Ruan; Stephen D. Nimer; Peng Yu; Xi Chen; Mingjiang Xu; Feng Chun Yang

doi:10.1126/sciadv.1601602

ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

Zhaomin Li, Peng Zhang, Aimin Yan, Zhengyu Guo, Yuguang Ban, Jin Li, Shi Chen, Hui Yang, Yongzheng He, Jianping Li, Ying Guo, Wen Zhang, Ehsan Hajiramezanali, Huangda An, Darlene Fajardo, J. William Harbour, Yijun Ruan, Stephen D. Nimer, Peng Yu, Xi ChenMingjiang Xu, Feng Chun Yang

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Abstract

ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin⁻cKit⁺ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.

Original language	English (US)
Article number	e1601602
Journal	Science Advances
Volume	3
Issue number	1
DOIs	https://doi.org/10.1126/sciadv.1601602
State	Published - Jan 2017
Externally published	Yes

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Li, Z., Zhang, P., Yan, A., Guo, Z., Ban, Y., Li, J., Chen, S., Yang, H., He, Y., Li, J., Guo, Y., Zhang, W., Hajiramezanali, E., An, H., Fajardo, D., William Harbour, J., Ruan, Y., Nimer, S. D., Yu, P., ... Yang, F. C. (2017). ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis. Science Advances, 3(1), Article e1601602. https://doi.org/10.1126/sciadv.1601602

Li, Z, Zhang, P, Yan, A, Guo, Z, Ban, Y, Li, J, Chen, S, Yang, H, He, Y, Li, J, Guo, Y, Zhang, W, Hajiramezanali, E, An, H, Fajardo, D, William Harbour, J, Ruan, Y, Nimer, SD, Yu, P, Chen, X, Xu, M & Yang, FC 2017, 'ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis', Science Advances, vol. 3, no. 1, e1601602. https://doi.org/10.1126/sciadv.1601602

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title = "ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis",

abstract = "ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin−cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.",

author = "Zhaomin Li and Peng Zhang and Aimin Yan and Zhengyu Guo and Yuguang Ban and Jin Li and Shi Chen and Hui Yang and Yongzheng He and Jianping Li and Ying Guo and Wen Zhang and Ehsan Hajiramezanali and Huangda An and Darlene Fajardo and {William Harbour}, J. and Yijun Ruan and Nimer, {Stephen D.} and Peng Yu and Xi Chen and Mingjiang Xu and Yang, {Feng Chun}",

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year = "2017",

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doi = "10.1126/sciadv.1601602",

language = "English (US)",

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AU - Li, Zhaomin

AU - Zhang, Peng

AU - Yan, Aimin

AU - Guo, Zhengyu

AU - Ban, Yuguang

AU - Li, Jin

AU - Chen, Shi

AU - Yang, Hui

AU - He, Yongzheng

AU - Li, Jianping

AU - Guo, Ying

AU - Zhang, Wen

AU - Hajiramezanali, Ehsan

AU - An, Huangda

AU - Fajardo, Darlene

AU - William Harbour, J.

AU - Ruan, Yijun

AU - Nimer, Stephen D.

AU - Yu, Peng

AU - Chen, Xi

AU - Xu, Mingjiang

AU - Yang, Feng Chun

PY - 2017/1

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N2 - ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin−cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.

AB - ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome–like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin−cKit+ (LK) cells. We have shown that loss of Asxl1 reduces the genome binding of RAD21 and SMC1A and alters the expression of ASXL1/cohesin target genes in LK cells. Our study underscores the ASXL1-cohesin interaction as a novel means to maintain normal sister chromatid separation and regulate gene expression in hematopoietic cells.

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ASXL1 interacts with the cohesin complex to maintain chromatid separation and gene expression for normal hematopoiesis

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