Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype.
Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype.
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DOI：
10.1073/pnas.2022760118
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发表时间：
2021-04-20
影响因子：
11.1
通讯作者：
Ley TJ
中科院分区：
文献类型：
--
作者：
Chen DY;Ferguson IM;Braun KA;Sutton LA;Helton NM;Ramakrishnan SM;Smith AM;Miller CA;Ley TJ
角质形成细胞癌是浅肤色患者中最常见的恶性肿瘤。年龄增长和日晒是皮肤癌的重要危险因素，并且与人类表皮中DNA甲基化缺失有关。小鼠皮肤中Dnmt3a完全缺乏会导致一种癌前状态，但造成这种现象的机制尚不清楚。本研究表明，小鼠表皮中Dnmt3a缺乏会导致局部的、典型的DNA低甲基化以及具有增殖基因表达特征的细胞比例增加。了解导致癌前状态的机制对于确定皮肤癌的新型预防或治疗策略可能很重要。
DNA低甲基化是老年及日晒皮肤表皮细胞的一个特征，但导致这种甲基化缺失的机制尚不清楚。Dnmt3a是皮肤中主要的从头DNA甲基转移酶；虽然表皮Dnmt3a缺乏会导致一种癌前状态，在此状态下角质形成细胞更容易被局部诱变剂转化，但导致这种转化易感性增加的条件尚未得到很好的理解。通过全基因组亚硫酸氢盐测序，我们在Dnmt3a缺陷小鼠的表皮细胞中发现了一种局部的、典型的DNA低甲基化表型。单细胞转录组分析显示，具有增殖基因表达特征的细胞比例增加，而皮肤中的其他细胞群相对没有变化。尽管在人类疾病状态中尚未描述过完全的DNMT3A缺乏，但患有与行为异常相关的过度生长综合征且癌症风险增加的罕见患者，其DNMT3A常常存在杂合的种系突变，从而使其功能降低（塔顿 - 布朗·拉赫曼综合征[TBRS]）。我们评估了一名具有种系DNMT3AR882H突变的TBRS患者皮肤的DNA甲基化表型，该突变编码一种显性负性蛋白，使其甲基转移酶功能降低约80%。我们检测到一种局部的、典型的低甲基化表型，它与在Dnmt3a缺陷小鼠皮肤中发现的低甲基化区域有相当大的重叠。总之，这些数据表明，DNMT3A缺失会在皮肤中产生一种与过度增殖表型相关的癌前表观遗传状态，并进一步表明DNMT3A在皮肤中起到肿瘤抑制作用。
Keratinocyte carcinomas are the most common malignancies in fair-skinned patients. Increased age and sun exposure are important skin cancer risk factors and have been associated with a loss of DNA methylation in the human epidermis. Complete Dnmt3a deficiency in mouse skin creates a premalignant state, but the mechanisms responsible for this phenomenon are not clear. This study demonstrates that Dnmt3a deficiency in murine epidermis causes focal, canonical DNA hypomethylation and an increased proportion of cells with a proliferative gene expression signature. Understanding the mechanisms responsible for the premalignant state may be important for defining novel preventative or therapeutic strategies for skin cancers. DNA hypomethylation is a feature of epidermal cells from aged and sun-exposed skin, but the mechanisms responsible for this methylation loss are not known. Dnmt3a is the dominant de novo DNA methyltransferase in the skin; while epidermal Dnmt3a deficiency creates a premalignant state in which keratinocytes are more easily transformed by topical mutagens, the conditions responsible for this increased susceptibility to transformation are not well understood. Using whole genome bisulfite sequencing, we identified a focal, canonical DNA hypomethylation phenotype in the epidermal cells of Dnmt3a-deficient mice. Single-cell transcriptomic analysis revealed an increased proportion of cells with a proliferative gene expression signature, while other populations in the skin were relatively unchanged. Although total DNMT3A deficiency has not been described in human disease states, rare patients with an overgrowth syndrome associated with behavioral abnormalities and an increased risk of cancer often have heterozygous, germline mutations in DNMT3A that reduce its function (Tatton-Brown Rahman syndrome [TBRS]). We evaluated the DNA methylation phenotype of the skin from a TBRS patient with a germline DNMT3AR882H mutation, which encodes a dominant-negative protein that reduces its methyltransferase function by ∼80%. We detected a focal, canonical hypomethylation phenotype that revealed considerable overlap with hypomethylated regions found in Dnmt3a-deficient mouse skin. Together, these data suggest that DNMT3A loss creates a premalignant epigenetic state associated with a hyperproliferative phenotype in the skin and further suggest that DNMT3A acts as a tumor suppressor in the skin.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
64.8
作者：
Bick AG;Weinstock JS;Nandakumar SK;Fulco CP;Bao EL;Zekavat SM;Szeto MD;Liao X;Leventhal MJ;Nasser J;Chang K;Laurie C;Burugula BB;Gibson CJ;Lin AE;Taub MA;Aguet F;Ardlie K;Mitchell BD;Barnes KC;Moscati A;Fornage M;Redline S;Psaty BM;Silverman EK;Weiss ST;Palmer ND;Vasan RS;Burchard EG;Kardia SLR;He J;Kaplan RC;Smith NL;Arnett DK;Schwartz DA;Correa A;de Andrade M;Guo X;Konkle BA;Custer B;Peralta JM;Gui H;Meyers DA;McGarvey ST;Chen IY;Shoemaker MB;Peyser PA;Broome JG;Gogarten SM;Wang FF;Wong Q;Montasser ME;Daya M;Kenny EE;North KE;Launer LJ;Cade BE;Bis JC;Cho MH;Lasky-Su J;Bowden DW;Cupples LA;Mak ACY;Becker LC;Smith JA;Kelly TN;Aslibekyan S;Heckbert SR;Tiwari HK;Yang IV;Heit JA;Lubitz SA;Johnsen JM;Curran JE;Wenzel SE;Weeks DE;Rao DC;Darbar D;Moon JY;Tracy RP;Buth EJ;Rafaels N;Loos RJF;Durda P;Liu Y;Hou L;Lee J;Kachroo P;Freedman BI;Levy D;Bielak LF;Hixson JE;Floyd JS;Whitsel EA;Ellinor PT;Irvin MR;Fingerlin TE;Raffield LM;Armasu SM;Wheeler MM;Sabino EC;Blangero J;Williams LK;Levy BD;Sheu WH;Roden DM;Boerwinkle E;Manson JE;Mathias RA;Desai P;Taylor KD;Johnson AD;NHLBI Trans-Omics for Precision Medicine Consortium;Auer PL;Kooperberg C;Laurie CC;Blackwell TW;Smith AV;Zhao H;Lange E;Lange L;Rich SS;Rotter JI;Wilson JG;Scheet P;Kitzman JO;Lander ES;Engreitz JM;Ebert BL;Reiner AP;Jaiswal S;Abecasis G;Sankaran VG;Kathiresan S;Natarajan P
通讯作者：
Natarajan P
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
DOI：
10.1126/science.aau3879
发表时间：
2018-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH
通讯作者：
Jones PH
DOI：
10.1158/1078-0432.ccr-14-1773
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li YY;Hanna GJ;Laga AC;Haddad RI;Lorch JH;Hammerman PS
通讯作者：
Hammerman PS