Heterochromatin marks HP1γ, HP1α and H3K9me3, and DNA damage response activation in human testis development and germ cell tumours

被引:14
作者
Bartkova, J. [1 ,2 ]
Moudry, P. [3 ]
Hodny, Z. [3 ]
Lukas, J. [1 ,2 ]
Rajpert-De Meyts, E. [4 ]
Bartek, J. [1 ,2 ]
机构
[1] Danish Canc Soc, Inst Canc Biol, DK-2100 Copenhagen O, Denmark
[2] Danish Canc Soc, Ctr Genotox Stress Res, DK-2100 Copenhagen O, Denmark
[3] Acad Sci Czech Republ, Inst Mol Genet, Dept Genome Integr, Prague, Czech Republic
[4] Rigshosp, Univ Dept Growth & Reprod, DK-2100 Copenhagen, Denmark
来源
INTERNATIONAL JOURNAL OF ANDROLOGY | 2011年 / 34卷 / 04期
基金
新加坡国家研究基金会;
关键词
DNA damage response; heterochromatin; heterochromatin protein 1; spermatogenesis; testicular germ cell neoplasms; trimethylated histone H3 at lysine 9; CARCINOMA-IN-SITU; ONCOGENE-INDUCED SENESCENCE; GENE-EXPRESSION; XY BODY; CANCER; BARRIER; BIOLOGY; BREAST; HP1; DEREGULATION;
D O I
10.1111/j.1365-2605.2010.01096.x
中图分类号
R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
摘要
Heterochromatinization has been implicated in fundamental biological and pathological processes including differentiation, senescence, ageing and tumourigenesis; however, little is known about its regulation and roles in human cells and tissues in vivo. Here, we show distinct cell-type-and cancer-stage-associated patterns of key heterochromatin marks: histone H3 trimethylated at lysine 9 (H3K9me3) and heterochromatic adaptor proteins HP1 alpha and HP1 gamma, compared with the gamma H2AX marker of endogenously activated DNA damage response (DDR) and proliferation markers in normal human foetal (n = 4) and adult (n = 29) testes, pre-invasive carcinoma in situ (CIS; n = 26) lesions and a series of overt germ cell tumours, including seminomas (n = 26), embryonal carcinomas (n = 18) and teratomas (n = 11). Among striking findings were high levels of HP1 gamma in foetal gonocytes, CIS and seminomas; enhanced multimarker heterochromatinization without DDR activation in CIS; and enhanced HP1 alpha in teratoma structures with epithelial and neuronal differentiation. Differential expression of the three heterochromatin markers suggests their partly non-overlapping roles, and separation of heterochromatinization from DDR activation highlights distinct responses of germ cells vs. somatic tissues in early tumourigenesis. Conceptually interesting findings were that subsets of human cells in vivo proliferate despite enhanced heterochromatinization, and that cells can strongly express even multiple heterochromatin features in the absence of functional retinoblastoma protein and without DDR activation. Overall, these results provide novel insights into cell-related and tumour-related diversity of heterochromatin in human tissues in vivo, relevant for andrology and intrinsic anti-tumour defence roles attributed to activated DDR and cellular senescence.
引用
收藏
页码:E103 / E113
页数:11
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