Cohesin-dependent regulation of Runx genes.
Runx transcription factors determine cell fate in many lineages. Maintaining balanced levels of Runx proteins is crucial, as deregulated expression leads to cancers and developmental disorders. We conducted a forward genetic screen in zebrafish for positive regulators of runx1 that yielded the cohesin subunit rad21. Zebrafish embryos lacking Rad21, or cohesin subunit Smc3, fail to express runx3 and lose hematopoietic runx1 expression in early embryonic development. Failure to develop differentiated blood cells in rad21 mutants is partially rescued by microinjection of runx1 mRNA. Significantly, monoallelic loss of rad21 caused a reduction in the transcription of runx1 and of the proneural genes ascl1a and ascl1b, indicating that downstream genes are sensitive to Rad21 dose. Changes in gene expression were observed in a reduced cohesin background in which cell division was able to proceed, indicating that cohesin might have a function in transcription that is separable from its mitotic role. Cohesin is a protein complex essential for sister chromatid cohesion and DNA repair that also appears to be essential for normal development through as yet unknown mechanisms. Our findings provide evidence for a novel role for cohesin in development, and indicate potential for monoallelic loss of cohesin subunits to alter gene expression.
Horsfield
Julia A
JA
Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Anagnostou
Sasha H
SH
Hu
Jimmy Kuang-Hsien
JK
Cho
Kitty Hsiao Yu
KH
Geisler
Robert
R
Lieschke
Graham
G
Crosier
Kathryn E
KE
Crosier
Philip S
PS
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001773:Blood Cells / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002842:Chromatids / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000502:physiology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis*; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis; D008938:Mitosis; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000378:metabolism; D000097722:Cohesins
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D009687:Nuclear Proteins; D021122:Protein Subunits; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000097722:Cohesins; C468127:Ascl1a protein, zebrafish; C472526:runx1 protein, zebrafish; C472527:runx3 protein, zebrafish