DNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs

被引：46

作者：

Guo, Hongshan ^{[1
,2
,11
,12
]}

Vuille, Joanna A. ^{[1
]}

Wittner, Ben S. ^{[1
]}

Lachtara, Emily M. ^{[1
]}

Hou, Yu ^{[3
,4
,11
,12
]}

Lin, Maoxuan ^{[1
,4
]}

Zhao, Ting ^{[1
,5
]}

Raman, Ayush T. ^{[1
,4
]}

Russell, Hunter C. ^{[1
]}

Reeves, Brittany A. ^{[1
]}

Pleskow, Haley M. ^{[1
,6
]}

Wu, Chin-Lee ^{[1
,5
]}

Gnirke, Andreas ^{[4
]}

Meissner, Alexander ^{[4
,7
]}

Efstathiou, Jason A. ^{[1
,6
]}

Lee, Richard J. ^{[1
,8
]}

Toner, Mehmet ^{[9
,10
]}

Aryee, Martin J. ^{[1
,5
,13
]}

Lawrence, Michael S. ^{[1
,4
,5
]}

Miyamoto, David T. ^{[1
,6
]}

Maheswaran, Shyamala ^{[1
,9
]}

Haber, Daniel A. ^{[1
,2
,8
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA 02129 USA

[7] Max Planck Inst Mol Genet, Dept Genome Regulat, D-14195 Berlin, Germany

[8] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[9] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[10] Harvard Med Sch, Shriners Hosp Children, Ctr Engn Med, Boston, MA 02114 USA

[11] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Bone Marrow Transplantat Ctr, Hangzhou 310012, Peoples R China

[12] Zhejiang Univ, Med Ctr, Liangzhu Lab, Hangzhou 310012, Peoples R China

[13] Harvard Med Sch, Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02114 USA

来源：

CELL | 2023年 / 186卷 / 13期

关键词：

CPG ISLAND HYPERMETHYLATION; RNA-SEQ; BASAL-CELLS; NKT CELLS; METHYLATION; PROGRESSION; EXPRESSION; ADENOCARCINOMA; QUANTIFICATION; ASSOCIATION;

D O I：

10.1016/j.cell.2023.05.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cancer is characterized by hypomethylation-associated silencing of large chromatin domains, whose contri-bution to tumorigenesis is uncertain. Through high-resolution genome-wide single-cell DNA methylation sequencing, we identify 40 core domains that are uniformly hypomethylated from the earliest detectable stages of prostate malignancy through metastatic circulating tumor cells (CTCs). Nested among these repressive domains are smaller loci with preserved methylation that escape silencing and are enriched for cell proliferation genes. Transcriptionally silenced genes within the core hypomethylated domains are en-riched for immune-related genes; prominent among these is a single gene cluster harboring all five CD1 genes that present lipid antigens to NKT cells and four IFI16-related interferon-inducible genes implicated in innate immunity. The re-expression of CD1 or IFI16 murine orthologs in immuno-competent mice abro-gates tumorigenesis, accompanied by the activation of anti-tumor immunity. Thus, early epigenetic changes may shape tumorigenesis, targeting co-located genes within defined chromosomal loci. Hypomethylation domains are detectable in blood specimens enriched for CTCs.

引用

页码：2765 / +

页数：47

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