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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 cis-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 cis-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. [ABSTRACT FROM AUTHOR]

Nephron progenitor number determines nephron endowment; a reduced nephron count is linked to the onset of kidney disease. Several transcriptional regulators including Six2, Wt1, Osr1, Sall1, Eya1, Pax2, and Hox11 paralogues are required for specification and/or maintenance of nephron progenitors. However, little is known about the regulatory intersection of these players. Here, we have mapped nephron progenitor-specific transcriptional networks of Six2, Hoxd11, Osr1, and Wt1. We identified 373 multi-factor associated ‘regulatory hotspots’ around genes closely associated with progenitor programs. To examine their functional significance, we deleted ‘hotspot’ enhancer elements for Six2 and Wnt4. Removal of the distal enhancer for Six2 leads to a ~40% reduction in Six2 expression. When combined with a Six2 null allele, progeny display a premature depletion of nephron progenitors. Loss of the Wnt4 enhancer led to a significant reduction of Wnt4 expression in renal vesicles and a mildly hypoplastic kidney, a phenotype also enhanced in combination with a Wnt4 null mutation. To explore the regulatory landscape that supports proper target gene expression, we performed CTCF ChIP-seq to identify insulator-boundary regions. One such putative boundary lies between the Six2 and Six3 loci. Evidence for the functional significance of this boundary was obtained by deep sequencing of the radiation-induced Brachyrrhine (Br) mutant allele. We identified an inversion of the Six2/Six3 locus around the CTCF-bound boundary, removing Six2 from its distal enhancer regulation, but placed next to Six3 enhancer elements which support ectopic Six2 expression in the lens where Six3 is normally expressed. Six3 is now predicted to fall under control of the Six2 distal enhancer. Consistent with this view, we observed ectopic Six3 in nephron progenitors. 4C-seq supports the model for Six2 distal enhancer interactions in wild-type and Br/+ mouse kidneys. Together, these data expand our view of the regulatory genome and regulatory landscape underpinning mammalian nephrogenesis. [ABSTRACT FROM AUTHOR]