Heritable, Allele-Specific Chromosomal Looping between Tandem Promoters Specifies Promoter Usage of SHC1

Xichuan Li; Zhenzhen Lin; Hao Wang; Dan Zhao; Xing Xu; Yiliang Wei; Xiaoting Li; Xiaobo Li; Yougui Xiang; Lance S Terada; Zhe Liu

doi:10.1128/MCB.00658-17

Heritable, Allele-Specific Chromosomal Looping between Tandem Promoters Specifies Promoter Usage of SHC1

Mol Cell Biol. 2018 Apr 16;38(9):e00658-17. doi: 10.1128/MCB.00658-17. Print 2018 May 1.

Authors

Xichuan Li^#^{1

2

3}, Zhenzhen Lin^#^{1

2

3}, Hao Wang^#^{1

2

3}, Dan Zhao^{1

2

3}, Xing Xu^{1

2

3}, Yiliang Wei^{1

2

3}, Xiaoting Li^{1

2

3}, Xiaobo Li^{1

2

3}, Yougui Xiang^{1

2

3}, Lance S Terada⁴, Zhe Liu^{5

2

3}

Affiliations

¹ Department of Immunology, Tianjin Key Laboratory of Medical Epigenetics, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
² Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University, Tianjin, China.
³ Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
⁴ Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁵ Department of Immunology, Tianjin Key Laboratory of Medical Epigenetics, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China zheliu@tmu.edu.cn.

^# Contributed equally.

Abstract

One-half of the genes in the human genome contain alternative promoters, some of which generate products with opposing functions. Aberrant silencing or activation of such alternative promoters is associated with multiple diseases, including cancer, but little is known regarding the molecular mechanisms that control alternative promoter choice. The SHC1 gene encodes p46^Shc/p52^Shc and p66^Shc, proteins oppositely regulating anchorage-independent growth that are produced by transcription initiated from the upstream and downstream tandem promoters of SHC1, respectively. Here we demonstrate that activation of these promoters is mutually exclusive on separate alleles in single primary endothelial cells in a heritable fashion, ensuring expression of both transcripts by the cell. Peripheral blood lymphocytes that do not transcribe p66^Shc transcribed p52^Shc biallelically. This distinct monoallelic transcription pattern is established by allele-specific chromosomal looping between tandem promoters, which silences the upstream promoter. Our results reveal a new mechanism to control alternative promoter usage through higher-order chromatin structure.

Keywords: SHC1; allele-specific transcription; alternative promoter interaction; gene silencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alleles
Chromatin / physiology
Endothelial Cells
Gene Expression Regulation / genetics
Human Umbilical Vein Endothelial Cells
Humans
Primary Cell Culture
Promoter Regions, Genetic / genetics
Src Homology 2 Domain-Containing, Transforming Protein 1 / genetics*
Src Homology 2 Domain-Containing, Transforming Protein 1 / physiology*
Transcriptional Activation / genetics*

Substances

Chromatin
SHC1 protein, human
Src Homology 2 Domain-Containing, Transforming Protein 1

Grants and funding

R01 CA208620/CA/NCI NIH HHS/United States