KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis.
KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis.
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DOI：
10.1101/gad.306241.117
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发表时间：
2018-01-15
影响因子：
10.5
通讯作者：
Capell BC
中科院分区：
文献类型：
--
作者：
Lin-Shiao E;Lan Y;Coradin M;Anderson A;Donahue G;Simpson CL;Sen P;Saffie R;Busino L;Garcia BA;Berger SL;Capell BC
在这项研究中，Lin-Shiao等人鉴定了KMT 2D（一种表观遗传调节因子）在协调自我更新、增殖和分化中的新作用，因为从未分化的表皮角质形成细胞中消耗KMT 2D会导致增殖减少、终末分化基因的过早假性激活和表皮分层紊乱。他们的结果揭示了KMT 2D在控制上皮增强子和p63靶基因表达中的关键作用，包括KMT 2D维持上皮祖细胞基因表达和协调适当的终末分化的需要。上皮组织依赖于自我更新、增殖和分化之间高度协调的平衡，其破坏可能驱动癌发生。表观遗传调节因子KMT 2D（MLL 4）是所有癌症中最常见的突变基因之一，特别是上皮癌，但其在这些组织中的正常功能尚不清楚。在这里，我们确定了一个新的作用KMT 2D在协调这种精细的平衡，从未分化的表皮角质形成细胞的KMT 2D的耗竭导致增殖减少，过早的假激活的终末分化基因，和混乱的表皮分层。全基因组范围内，KMT 2D与p63相互作用，并在其靶增强子处富集。KMT 2D的消耗导致增强子组蛋白修饰H3 Lys 4（H3 K4）单甲基化（H3 K4 me 1）和H3 K27乙酰化（H3 K27 ac）的广泛丧失，以及p63靶基因（包括参与上皮发育和粘附的关键基因）表达的降低。总之，这些结果揭示了KMT 2D在控制上皮增强子和p63靶基因表达中的关键作用，包括KMT 2D维持上皮祖细胞基因表达和协调适当的终末分化的需要。
In this study, Lin-Shiao et al. identify a novel role for KMT2D, an epigenetic regulator, in coordinating self-renewal, proliferation, and differentiation, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Their results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation. Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation, disruption of which may drive carcinogenesis. The epigenetic regulator KMT2D (MLL4) is one of the most frequently mutated genes in all cancers, particularly epithelial cancers, yet its normal function in these tissues is unknown. Here, we identify a novel role for KMT2D in coordinating this fine balance, as depletion of KMT2D from undifferentiated epidermal keratinocytes results in reduced proliferation, premature spurious activation of terminal differentiation genes, and disorganized epidermal stratification. Genome-wide, KMT2D interacts with p63 and is enriched at its target enhancers. Depletion of KMT2D results in a broad loss of enhancer histone modifications H3 Lys 4 (H3K4) monomethylation (H3K4me1) and H3K27 acetylation (H3K27ac) as well as reduced expression of p63 target genes, including key genes involved in epithelial development and adhesion. Together, these results reveal a critical role for KMT2D in the control of epithelial enhancers and p63 target gene expression, including the requirement of KMT2D for the maintenance of epithelial progenitor gene expression and the coordination of proper terminal differentiation.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1126/science.1242281
发表时间：
2014-06-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Blanpain C;Fuchs E
通讯作者：
Fuchs E
影响因子：
11.2
作者：
Kim JH;Sharma A;Dhar SS;Lee SH;Gu B;Chan CH;Lin HK;Lee MG
通讯作者：
Lee MG
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
1.1
作者：
Eckert RL;Adhikary G;Young CA;Jans R;Crish JF;Xu W;Rorke EA
通讯作者：
Rorke EA