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Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ϵ-Globin Gene Expression.

Production of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ϵ-, and γ-globin genes, switches from ϵ-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human... Full description

Journal Title: The Journal of biological chemistry March 24, 2017, Vol.292(12), pp.4811-4817
Main Author: Wang, Yadong
Other Authors: Wang, Ying , Ma, Lingling , Nie, Min , Ju, Junyi , Liu, Ming , Deng, Yexuan , Yao, Bing , Gui, Tao , Li, Xinyu , Guo, Chan , Ma, Chi , Tan, Renxiang , Zhao, Quan
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1083-351X ; DOI: 10.1074/jbc.M116.768515
Link: http://search.proquest.com/docview/1865557041/?pq-origsite=primo
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title: Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ϵ-Globin Gene Expression.
format: Article
creator:
  • Wang, Yadong
  • Wang, Ying
  • Ma, Lingling
  • Nie, Min
  • Ju, Junyi
  • Liu, Ming
  • Deng, Yexuan
  • Yao, Bing
  • Gui, Tao
  • Li, Xinyu
  • Guo, Chan
  • Ma, Chi
  • Tan, Renxiang
  • Zhao, Quan
subjects:
  • Cell Line–Metabolism
  • Chromosomal Proteins, Non-Histone–Metabolism
  • DNA Methylation–Genetics
  • Epigenetic Repression–Genetics
  • Histone-Lysine N-Methyltransferase–Genetics
  • Humans–Genetics
  • Promoter Regions, Genetic–Genetics
  • Transcriptional Activation–Genetics
  • Epsilon-Globins–Genetics
  • Cbx3 Protein, Human
  • Chromosomal Proteins, Non-Histone
  • Epsilon-Globins
  • Heterochromatin-Specific Nonhistone Chromosomal Protein Hp-1
  • Histone-Lysine N-Methyltransferase
  • Kmt5c Protein, Human
  • DNA Methylation
  • H4k20me3
  • Hp1γ
  • Suv4–20h2
ispartof: The Journal of biological chemistry, March 24, 2017, Vol.292(12), pp.4811-4817
description: Production of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ϵ-, and γ-globin genes, switches from ϵ-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human ϵ-globin in mice has been shown to ameliorate anemia caused by β-globin mutations, including those causing β-thalassemia and sickle cell disease, raising the prospect that reactivation of ϵ-globin expression could be used in managing these conditions in humans. Although the human globin genes are known to be regulated by a variety of multiprotein complexes containing enzymes that catalyze epigenetic modifications, the exact mechanisms controlling ϵ-globin gene silencing remain elusive. Here we found that the heterochromatin protein HP1γ, a multifunctional chromatin- and DNA-binding protein with roles in transcriptional activation and elongation, represses ϵ-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4-20h2. Silencing of HP1γ expression markedly decreased repressive histone marks and the multimethylation of histone H3 lysine 9 and H4 lysine 20, leading to a significant decrease in DNA methylation at the proximal promoter of the ϵ-globin gene and greatly increased ϵ-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1γ on the ϵ-globin-proximal promoter. Thus, these data indicate that HP1γ is a novel epigenetic repressor of ϵ-globin gene expression and provide a potential strategy for targeted therapies for β-thalassemia and sickle cell disease.
language: eng
source:
identifier: E-ISSN: 1083-351X ; DOI: 10.1074/jbc.M116.768515
fulltext: fulltext
issn:
  • 1083351X
  • 1083-351X
url: Link


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titleHeterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ϵ-Globin Gene Expression.
creatorWang, Yadong ; Wang, Ying ; Ma, Lingling ; Nie, Min ; Ju, Junyi ; Liu, Ming ; Deng, Yexuan ; Yao, Bing ; Gui, Tao ; Li, Xinyu ; Guo, Chan ; Ma, Chi ; Tan, Renxiang ; Zhao, Quan
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ispartofThe Journal of biological chemistry, March 24, 2017, Vol.292(12), pp.4811-4817
identifierE-ISSN: 1083-351X ; DOI: 10.1074/jbc.M116.768515
subjectCell Line–Metabolism ; Chromosomal Proteins, Non-Histone–Metabolism ; DNA Methylation–Genetics ; Epigenetic Repression–Genetics ; Histone-Lysine N-Methyltransferase–Genetics ; Humans–Genetics ; Promoter Regions, Genetic–Genetics ; Transcriptional Activation–Genetics ; Epsilon-Globins–Genetics ; Cbx3 Protein, Human ; Chromosomal Proteins, Non-Histone ; Epsilon-Globins ; Heterochromatin-Specific Nonhistone Chromosomal Protein Hp-1 ; Histone-Lysine N-Methyltransferase ; Kmt5c Protein, Human ; DNA Methylation ; H4k20me3 ; Hp1γ ; Suv4–20h2
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descriptionProduction of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ϵ-, and γ-globin genes, switches from ϵ-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human ϵ-globin in mice has been shown to ameliorate anemia caused by β-globin mutations, including those causing β-thalassemia and sickle cell disease, raising the prospect that reactivation of ϵ-globin expression could be used in managing these conditions in humans. Although the human globin genes are known to be regulated by a variety of multiprotein complexes containing enzymes that catalyze epigenetic modifications, the exact mechanisms controlling ϵ-globin gene silencing remain elusive. Here we found that the heterochromatin protein HP1γ, a multifunctional chromatin- and DNA-binding protein with roles in transcriptional activation and elongation, represses ϵ-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4-20h2. Silencing of HP1γ expression markedly decreased repressive histone marks and the multimethylation of histone H3 lysine 9 and H4 lysine 20, leading to a significant decrease in DNA methylation at the proximal promoter of the ϵ-globin gene and greatly increased ϵ-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1γ on the ϵ-globin-proximal promoter. Thus, these data indicate that HP1γ is a novel epigenetic repressor of ϵ-globin gene expression and provide a potential strategy for targeted therapies for β-thalassemia and sickle cell disease.
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authorWang, Yadong ; Wang, Ying ; Ma, Lingling ; Nie, Min ; Ju, Junyi ; Liu, Ming ; Deng, Yexuan ; Yao, Bing ; Gui, Tao ; Li, Xinyu ; Guo, Chan ; Ma, Chi ; Tan, Renxiang ; Zhao, Quan
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