SIRT1 deacetylates SATB1 to facilitate MAR HS2-MAR ε interaction and promote ε-globin expression.
The higher order chromatin structure has recently been revealed as a critical new layer of gene transcriptional control. Changes in higher order chromatin structures were shown to correlate with the availability of transcriptional factors and/or MAR (matrix attachment region) binding proteins, which tether genomic DNA to the nuclear matrix. How posttranslational modification to these protein organizers may affect higher order chromatin structure still pending experimental investigation. The type III histone deacetylase silent mating type information regulator 2, S. cerevisiae, homolog 1 (SIRT1) participates in many physiological processes through targeting both histone and transcriptional factors. We show that MAR binding protein SATB1, which mediates chromatin looping in cytokine, MHC-I and β-globin gene loci, as a new type of SIRT1 substrate. SIRT1 expression increased accompanying erythroid differentiation and the strengthening of β-globin cluster higher order chromatin structure, while knockdown of SIRT1 in erythroid k562 cells weakened the long-range interaction between two SATB1 binding sites in the β-globin locus, MAR(HS2) and MAR(ε). We also show that SIRT1 activity significantly affects ε-globin gene expression in a SATB1-dependent manner and that knockdown of SIRT1 largely blocks ε-globin gene activation during erythroid differentiation. Our work proposes that SIRT1 orchestrates changes in higher order chromatin structure during erythropoiesis, and reveals the dynamic higher order chromatin structure regulation at posttranslational modification level.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
Zheng
Z
Xue
Xiang
X
Lv
Wei
W
Song
Xing
X
Wang
Guang-Nian
GN
Zhao
Wen-Tian
WT
Wang
Jian
J
Xiong
Bei-Bei
BB
Mao
Wei
W
Yu
Ben
B
Yang
Jie
J
Wu
Li-Quan
LQ
Zhou
De-Long
DL
Hao
Wen-Ji
WJ
Dong
De-Pei
DP
Liu
Chih-Chuan
CC
Liang
D002478:Cells, Cultured; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D019901:Locus Control Region; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism*; D045170:Matrix Attachment Regions; D056564:Sirtuin 1 / Q000378:metabolism*; D055544:beta-Globins / Q000235:genetics; D055547:epsilon-Globins / Q000096:biosynthesis / Q000235:genetics*
D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human; D055544:beta-Globins; D055547:epsilon-Globins; D006427:Hemin; D056564:Sirtuin 1