Epigenetic control of region‐specific transcriptional programs in mouse cerebellar and cortical astrocytes

Welle, Anna; Kasakow, Carmen V.; Jungmann, Annemarie; Gobbo, Davide; Stopper, Laura; Nordström, Karl; Salhab, Abdulrahman; Gasparoni, Gilles; Scheller, Anja; Kirchhoff, Frank; Walter, Jörn

doi:10.1002/glia.24016

Cited by 19 publications

(13 citation statements)

References 92 publications

(169 reference statements)

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“…We calculated the regional variance of gene expression between NPCs and astrocytes from different regions (Fig. 2i) and found that FOXG1, OTX2, HOXB2, LHX2 as well as the ZIC- and IRX family define regionalization in both neuron and astrocyte populations, similar to observations in mouse and primary human tissue 25–29 (Extended Data Fig. 5a-g).…”

Section: Resultssupporting

confidence: 64%

Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency

Zenk,

Fleck,

Jansen

et al. 2023

Preprint

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Human cell type diversity emerges through a highly regulated series of fate restrictions from pluripotent progenitors. Fate restriction is orchestrated in part through epigenetic modifications at genes and regulatory elements, however it has been difficult to study these mechanisms in humans. Here, we use organoid models of the human central nervous system and establish single-cell profiling of histone modifications (H3K27ac, H3K27me3, H3K4me3) in organoid cells over a time course to reconstruct epigenomic trajectories governing cell identity acquisition from human pluripotency. We capture transitions from pluripotency through neuroepithelium, to retinal and brain region specification, as well as differentiation from progenitors to neuronal and glial terminal states. We find that switching of repressive and activating epigenetic modifications can precede and predict decisions at each stage, providing a temporal census of gene regulatory elements and transcription factors that we characterize in a gene regulatory network underlying human cerebral fate acquisition. We use transcriptome and chromatin accessibility measurements in the same cell from a human developing brain to validate this regulatory mode in a primary tissue. We show that abolishing histone 3 lysine 27 trimethylation (H3K27me3) through inhibition of the polycomb group protein Embryonic Ectoderm Development (EED) at the neuroectoderm stage disrupts fate restriction and leads to aberrant cell fate acquisition, ultimately influencing cell type composition in brain organoids. Altogether, our single-cell genome wide map of histone modifications during human neural organoid development serves as a blueprint (https://episcape.ethz.ch) to explore human cell fate decisions in normal physiology and in neurodevelopmental disorders. More broadly, this approach can be used to study human epigenomic trajectory mechanisms in any human organoid system.SummaryUnguided neural organoids reveal widespread and dynamic switching of epigenetic modifications during development and recapitulate fate restriction from pluripotency to terminally differentiated cells of the human central nervous system.

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Section: Resultssupporting

confidence: 64%

Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency

Zenk,

Fleck,

Jansen

et al. 2023

Preprint

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“…However, considering that the Mecp2 deficient brain suffers from complex molecular and functional defects, we believe that other indirect factors can participate to the described astrocyte heterogeneity. For instance, we can suggest that a diverse signature of DNA methylation might play a role in the heterogeneity among inter-regional astrocytes, as reported for cortical and cerebellar astrocytes ( Welle et al, 2021 ). Further, considering that a plethora of different post-translational modifications (PTMs) generates and regulates the functional versatility of MeCP2 ( Bellini et al, 2014 ), future studies should also investigate if different events of PTM affect Mecp2 functions in astrocytes.…”

Section: Discussionsupporting

confidence: 61%

Identification of Region-Specific Cytoskeletal and Molecular Alterations in Astrocytes of Mecp2 Deficient Animals

et al. 2022

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Rett syndrome (RTT) is a neurodevelopmental disorder that represents the most common genetic cause of severe intellectual disability in females. Most patients carry mutations in the X-linked MECP2 gene, coding for the methyl-CpG-binding protein 2 (MeCP2), originally isolated as an epigenetic transcriptional factor able to bind methylated DNA and repress transcription. Recent data implicated a role for glia in RTT, showing that astrocytes express Mecp2 and that its deficiency affects their ability to support neuronal maturation by non-cell autonomous mechanisms. To date, some molecular, structural and functional alterations have been attributed to Mecp2 null astrocytes, but how they evolve over time and whether they follow a spatial heterogeneity are two aspects which deserve further investigations. In this study, we assessed cytoskeletal features of astrocytes in Mecp2 deficient brains by analyzing their arbor complexity and processes in reconstructed GFAP+ cells at different ages, corresponding to peculiar stages of the disorder, and in different cerebral regions (motor and somatosensory cortices and CA1 layer of hippocampus). Our findings demonstrate the presence of defects in Mecp2 null astrocytes that worsen along disease progression and strictly depend on the brain area, highlighting motor and somatosensory cortices as the most affected regions. Of relevance, astrocyte cytoskeleton is impaired also in the somatosensory cortex of symptomatic heterozygous animals, with Mecp2+ astrocytes showing slightly more pronounced defects with respect to the Mecp2 null cells, emphasizing the importance of non-cell autonomous effects. We reported a temporal correlation between the progressive thinning of layer I and the atrophy of astrocytes, suggesting that their cytoskeletal dysfunctions might contribute to cortical defects. Considering the reciprocal link between morphology and function in astrocytes, we analyzed the effect of Mecp2 deficiency on the expression of selected astrocyte-enriched genes, which describe typical astrocytic features. qRT-PCR data corroborated our results, reporting an overall decrement of gene expression, which is area and age-dependent. In conclusion, our data show that Mecp2 deficiency causes structural and molecular alterations in astrocytes, which progress along with the severity of symptoms and diversely occur in the different cerebral regions, highlighting the importance of considering heterogeneity when studying astrocytes in RTT.

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“…At the epigenetic level, a wide range of transcriptionally active open chromatin is shared between GFAP + cortical astrocytes and Bergman glia ( Welle et al, 2021 ). Binding sites of the nuclear factor I (Nfi) family, known to promote astrocyte differentiation, are enriched in about 25% in these open chromatin regions.…”

Section: Astrocyte Maturationmentioning

confidence: 99%

“…Cortical astrocytes execute well specific transcriptional programs centralized around Lhx2 and FoxG1 that are epigenetically controlled. Even in the young adult mouse, astrocytes keep epigenetic marks from their region-restricted RGC specification ( Welle et al, 2021 ). By modeling astrogliogenesis from mouse stem cell coupled to next-generation sequencing and computational approaches, Tiwari and colleagues described regulatory elements and transcriptional programs underlying astrocyte generation and maturation as well as stage- and lineage-specific transcriptomic and epigenetic signatures.…”

Section: Astrocyte Maturationmentioning

confidence: 99%

Astrocyte development in the cerebral cortex: Complexity of their origin, genesis, and maturation

2022

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In the mammalian brain, astrocytes form a heterogeneous population at the morphological, molecular, functional, intra-, and inter-region levels. In the past, a few types of astrocytes have been first described based on their morphology and, thereafter, according to limited key molecular markers. With the advent of bulk and single-cell transcriptomics, the diversity of astrocytes is now progressively deciphered and its extent better appreciated. However, the origin of this diversity remains unresolved, even though many recent studies unraveled the specificities of astroglial development at both population and individual cell levels, particularly in the cerebral cortex. Despite the lack of specific markers for each astrocyte subtype, a better understanding of the cellular and molecular events underlying cortical astrocyte diversity is nevertheless within our reach thanks to the development of intersectional lineage tracing, microdissection, spatial mapping, and single-cell transcriptomic tools. Here we present a brief overview describing recent findings on the genesis and maturation of astrocytes and their key regulators during cerebral cortex development. All these studies have considerably advanced our knowledge of cortical astrogliogenesis, which relies on a more complex mode of development than their neuronal counterparts, that undeniably impact astrocyte diversity in the cerebral cortex.

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Epigenetic control of region‐specific transcriptional programs in mouse cerebellar and cortical astrocytes

Cited by 19 publications

References 92 publications

Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency

Single-cell epigenomic reconstruction of developmental trajectories in human neural organoid systems from pluripotency

Identification of Region-Specific Cytoskeletal and Molecular Alterations in Astrocytes of Mecp2 Deficient Animals

Astrocyte development in the cerebral cortex: Complexity of their origin, genesis, and maturation

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