Epigenetic regulation during human cortical development: Seq-ing answers from the brain to the organoid

Abstract

Epigenetic regulation plays an important role in controlling gene expression during complex processes, such as development of the human brain. Mutations in genes encoding chromatin modifying proteins and in the non-protein coding sequences of the genome can potentially alter transcription factor binding or chromatin accessibility. Such mutations can frequently cause neurodevelopmental disorders, therefore understanding how epigenetic regulation shapes brain development is of particular interest. While epigenetic regulation of neural development has been extensively studied in murine models, significant species-specific differences in both the genome sequence and in brain development necessitate human models. However, access to human fetal material is limited and these tissues cannot be grown or experimentally manipulated ex vivo . Therefore, models that recapitulate particular aspects of human fetal brain development, such as the in vitro differentiation of human pluripotent stem cells (hPSCs), are instrumental for studying the epigenetic regulation of human neural development. Here, we examine recent studies that have defined changes in the epigenomic landscape during fetal brain development. We compare these studies with analogous data derived by in vitro differentiation of hPSCs into specific neuronal cell types or as three-dimensional cerebral organoids. Such comparisons can be informative regarding which aspects of fetal brain development are faithfully recapitulated by in vitro differentiation models and provide a foundation for using experimentally tractable in vitro models of human brain development to study neural gene regulation and the basis of its disruption to cause neurodevelopmental disorders.

AUTS2 Syndrome: Molecular Mechanisms and Model Systems

“…Although ChIP-seq is a widely used method to evaluate global active and repressed chromatin states, it is limited by low signal-to-noise ratios and is not compatible with low cellular input–a potentially significant challenge for organoid applications ( Lewis et al, 2021 ). However, newer chromatin mapping methods such as CUT&RUN and CUT&Tag can be combined with scRNA-seq to target and profile specific chromatin signatures with single cell resolution ( Kaya-Okur et al, 2019 ; Yu et al, 2022 ).…”

Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

“…In addition, certain aspects of PcG regulation may be species-specific, requiring investigation in human model systems (E. M. A. Lewis et al, 2021;van de Werken et al, 2014). Examining PcG function in the context of human tissues, specifically during human neurogenesis, will require new experimental approaches.…”

“…The development of human iPSCs and advanced protocols for generation of brain organoids has drastically changed possibilities for neurodevelopmental research. Important aspects of early human brain development (Kelava & Lancaster, 2016; Mora‐Bermudez et al., 2016; Pollen et al., 2019), including cell morphology and tissue structure as well as gene expression patterns (Camp et al., 2015) and overall epigenomic landscape (Amiri et al., 2018; E. M. A. Lewis et al., 2021; Trevino et al., 2020) are recapitulated in these 3D in vitro models. There are various approaches on how to examine PcG activity and function in these advanced 3D cell culture systems as well as ex vivo in human primary tissue samples, some of which we will highlight here (Figure 6).…”

“…These studies suggest that intricate regulatory mechanisms at various levels from gene transcription to PcG complex composition influence the context‐specific activity of PcG proteins. In addition, certain aspects of PcG regulation may be species‐specific, requiring investigation in human model systems (E. M. A. Lewis et al., 2021; van de Werken et al., 2014). Examining PcG function in the context of human tissues, specifically during human neurogenesis, will require new experimental approaches.…”

Transgenerational Effects of Prenatal Ethanol Exposure in Prepubescent Mice

“…Indeed, several recent reports have suggested that phenotypic variation induced by PrEE can extend several generations ( Govorko et al, 2012 ; Gangisetty et al, 2020 ), likely via epigenetic mechanisms ( Chastain and Sarkar, 2017 ). Because precise epigenetic regulation, or the control of gene expression not related to changes in DNA sequence, is also crucial for complex development of the neocortex ( Adam and Harwell, 2020 ; Lewis et al, 2021 ) as well as how PrEE induces widespread epigenetic dysregulation in the brain ( Subbana et al, 2014 ; Öztürk et al, 2017 ), the notion that underlying epigenetic mechanisms may be driving transgenerational FASD phenotypes represents an attractive hypothesis.…”