Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA.
Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA.
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DOI：
10.1093/nar/gkx896
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发表时间：
2017-12-15
影响因子：
14.9
通讯作者：
Pfeifer K
中科院分区：
文献类型：
--
作者：
Park KS;Mitra A;Rahat B;Kim K;Pfeifer K
印迹基因发生在离散的集群中，这些集群由称为印迹控制区的共享DNA元件协调调节。H19和Igf2是相互关联的印迹基因，在发育过程中起着关键作用。母体染色体IGF2/H19位点印迹缺失（LOI）与发育障碍Beckwith Wiedemann综合征（BWS）和几种癌症有关。在这里，我们使用全面的遗传和基因组分析来跟踪BWS小鼠模型的肌肉发育，以剖析Igf2和H19错表达在疾病表型中的单独和共同作用。我们发现LOI导致肌肉分化和肥厚的缺陷，并确定了主要的下游靶点：Igf2过表达导致MAPK信号的过度激活，而H19 lncRNA的缺失阻止了p53活性的正常下调，从而导致AKT/mTOR信号的减少。此外，我们还展示了H19和Igf2错表达分别、合作和拮抗作用的例子，以建立发育表型。因此，本研究确定了H19 lncRNA的新的生化作用，并强调LOI表型是多基因的，因此复杂的相互作用将有助于疾病的预后。
Imprinted genes occur in discrete clusters that are coordinately regulated by shared DNA elements called Imprinting Control Regions. H19 and Igf2 are linked imprinted genes that play critical roles in development. Loss of imprinting (LOI) at the IGF2/H19 locus on the maternal chromosome is associated with the developmental disorder Beckwith Wiedemann Syndrome (BWS) and with several cancers. Here we use comprehensive genetic and genomic analyses to follow muscle development in a mouse model of BWS to dissect the separate and shared roles for misexpression of Igf2 and H19 in the disease phenotype. We show that LOI results in defects in muscle differentiation and hypertrophy and identify primary downstream targets: Igf2 overexpression results in over-activation of MAPK signaling while loss of H19 lncRNA prevents normal down regulation of p53 activity and therefore results in reduced AKT/mTOR signaling. Moreover, we demonstrate instances where H19 and Igf2 misexpression work separately, cooperatively, and antagonistically to establish the developmental phenotype. This study thus identifies new biochemical roles for the H19 lncRNA and underscores that LOI phenotypes are multigenic so that complex interactions will contribute to disease outcomes.
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DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
64.8
作者：
HAO, Y;CRENSHAW, T;TYCKO, B
通讯作者：
TYCKO, B
影响因子：
11.2
作者：
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通讯作者：
Penn, Linda Z.
影响因子：
7.2
作者：
Barlow, Denise P.;Bartolomei, Marisa S.
通讯作者：
Bartolomei, Marisa S.
影响因子：
10.5
作者：
Dey BK;Pfeifer K;Dutta A
通讯作者：
Dutta A