Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression
Unbiased, Genome-Wide In Vivo Mapping of Transcriptional Regulatory Elements Reveals Sex Differences in Chromatin Structure Associated with Sex-Specific Liver Gene Expression
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DOI：
10.1128/mcb.00601-10
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发表时间：
2010-12-01
影响因子：
5.3
通讯作者：
Waxman, David J.
中科院分区：
文献类型：
--
作者：
Ling, Guoyu;Sugathan, Aarathi;Waxman, David J.
我们已经使用了一种简单而有效的方法来确定条件特异性转录调控位点在体内，以帮助阐明转录，这是广泛存在于哺乳动物组织和影响正常生理，药物反应，炎症和疾病的性别相关差异的分子基础。为了系统地揭示负责这些差异的转录调节因子，我们使用DNase超敏反应分析结合高通量测序，在雄性和雌性小鼠肝脏以及通过连续输注生长激素（GH）雌性化的雄性小鼠肝脏中产生调节位点的条件特异性地图。我们确定了71，264个过敏部位，其中1，284个显示出与性别相关的差异。连续GH输注抑制了绝大多数男性特异性位点，并诱导了男性肝脏中女性特异性位点的子集。我们还确定了广泛的基因组区域（高达100 kb）显示性别依赖性超敏反应和类似的GH反应模式。我们发现性别特异性位点与性别特异性转录有很强的相关性;然而，大多数性别特异性位点距离性别特异性基因>100 kb。通过分析调控区域内的序列基序，我们确定了两个已知的肝脏性二态性的调节因子和几个新的候选人进行进一步的研究。这种方法可以很容易地应用于映射条件特异性调节位点在哺乳动物组织在各种各样的生理条件下。
We have used a simple and efficient method to identify condition-specific transcriptional regulatory sites in vivo to help elucidate the molecular basis of sex-related differences in transcription, which are widespread in mammalian tissues and affect normal physiology, drug response, inflammation, and disease. To systematically uncover transcriptional regulators responsible for these differences, we used DNase hypersensitivity analysis coupled with high-throughput sequencing to produce condition-specific maps of regulatory sites in male and female mouse livers and in livers of male mice feminized by continuous infusion of growth hormone (GH). We identified 71,264 hypersensitive sites, with 1,284 showing robust sex-related differences. Continuous GH infusion suppressed the vast majority of male-specific sites and induced a subset of female-specific sites in male livers. We also identified broad genomic regions (up to similar to 100 kb) showing sex-dependent hypersensitivity and similar patterns of GH responses. We found a strong association of sex-specific sites with sex-specific transcription; however, a majority of sex-specific sites were >100 kb from sex-specific genes. By analyzing sequence motifs within regulatory regions, we identified two known regulators of liver sexual dimorphism and several new candidates for further investigation. This approach can readily be applied to mapping condition-specific regulatory sites in mammalian tissues under a wide variety of physiological conditions.