Characterization of Gene Regulatory Elements in Human Fetal Cortical Development: Enhancing Our Understanding of Neurodevelopmental Disorders and Evolution

Abstract

The neocortex is the region that most distinguishes human brain from other mammals and primates [Annu Rev Genet. 2021 Nov;55(1):555–81]. Studying the development of human cortex is important in understanding the evolutionary changes occurring in humans relative to other primates, as well as in elucidating mechanisms underlying neurodevelopmental disorders. Cortical development is a highly regulated process, spatially and temporally coordinated by expression of essential transcriptional factors in response to signaling pathways [Neuron. 2019 Sep;103(6):980–1004]. Enhancers are the most well-understood <i>cis</i>-acting, non-protein-coding regulatory elements that regulate gene expression [Nat Rev Genet. 2014 Apr;15(4):272–86]. Importantly, given the conservation of both DNA sequence and molecular function of the majority of proteins across mammals [Genome Res. 2003 Dec;13(12):2507–18], enhancers [Science. 2015 Mar;347(6226):1155–9], which are far more divergent at the sequence level, likely account for the phenotypes that distinguish the human brain by changing the regulation of gene expression. In this review, we will revisit the conceptual framework of gene regulation during human brain development, as well as the evolution of technologies to study transcriptional regulation, with recent advances in genome biology that open a window allowing us to systematically characterize <i>cis</i>-regulatory elements in developing human brain [Hum Mol Genet. 2022 Oct;31(R1):R84–96]. We provide an update on work to characterize the suite of all enhancers in the developing human brain and the implications for understanding neuropsychiatric disorders. Finally, we discuss emerging therapeutic ideas that utilize our emerging knowledge of enhancer function.

From Vessels to Neurons—The Role of Hypoxia Pathway Proteins in Embryonic Neurogenesis

“…Any defect in the establishment of the stereotypical cortex microarchitecture has profound functional consequences and can lead to clinical symptoms, such as those present in intellectual disability or seizure disorders [24,83,84]. These perturbations may arise from intrinsic developmental impairments such as mutations in neurogenesis-related genes [24,83,85,86] but more commonly stem from the external environment, particularly nutrient deprivation or infections [87][88][89][90][91]. An efficient delivery of nutrients, including the metabolically necessary oxygen and glucose, requires a tightly spatiotemporally-regulated ingrowth of blood vessels.…”