A Chromatin Accessibility Atlas of the Developing Human Telencephalon.,Cell

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A Chromatin Accessibility Atlas of the Developing Human Telencephalon.
Cell ( IF 45.5 ) Pub Date : 2020-06-30 , DOI: 10.1016/j.cell.2020.06.002
Eirene Markenscoff-Papadimitriou ₁ , Sean Whalen ₂ , Pawel Przytycki ₂ , Reuben Thomas ₂ , Fadya Binyameen ₁ , Tomasz J Nowakowski ₃ , Arnold R Kriegstein ₄ , Stephan J Sanders ₅ , Matthew W State ₁ , Katherine S Pollard ₆ , John L Rubenstein ₁

Affiliation

Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Gladstone Institutes, San Francisco, CA, USA.
Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Gladstone Institutes, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biology Institute, University of California, San Francisco, San Francisco, CA, USA.

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.

中文翻译：

发育中的人类端脑染色质可及性图谱。

为了发现驱动人类大脑发育中不同细胞类型和区域基因表达特异性的调控元件，我们从妊娠中期人类端脑的九个解剖区域以及显微解剖的上层和深层大脑中生成了开放染色质图谱。前额皮质。我们确定了开放染色质区域 (OCR) 的一个子集，称为预测调节元件 (pRE)，它们可能起到大脑发育增强剂的作用。 pRE 显示染色质可及性的时间、区域和层状差异，并且与跨区域和孕龄的基因表达差异相关。我们在自闭症风险基因SLC6A1的 pRE 中鉴定了两个功能性从头变异，并使用 CRISPRa 证明了该 pRE 调节SCL6A1 。此外，小鼠转基因实验验证了FEZF2和BCL11A附近 pRE 的增强子活性。因此，该图谱可作为解码健康和疾病中神经发育基因调控的资源。

更新日期：2020-08-06

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