Biology subjects

Baizabal, J.-M.

Publications and source records attributed to Baizabal, J.-M..

3 recordsLinked to original sources

bioRxiv2026

Histone H3K9 Methyltransferases Regulate Cortical Growth by Coordinating Heterochromatin Formation and Neural Progenitor Dynamics

DNA packaging into heterochromatin is a fundamental mechanism of transcriptional silencing. However, how heterochromatin regulates neurogenesis in the developing cerebral cortex remains poorly understood. A defining feature of heterochromatin is trimethylation of histone H3 lysine 9 (H3K9me3), catalyzed by the H3K9 methyltransferases SETDB1, SUV39H1, and SUV39H2. Here, we generate a cortex-specific triple knockout mouse model lacking Setdb1, Suv39h1, and Suv39h2 to interrogate the collective functions of H3K9 methyltransferases and H3K9me3 during corticogenesis. Loss of H3K9 methyltransferases disrupts cell-cycle dynamics and cortical neurogenesis, resulting in microcephaly. We show that H3K9me3 is associated with the silencing of distinct gene families, lineage-inappropriate genes, and transposable elements, and that its loss is accompanied by local chromatin opening and enhanced transcription factor occupancy. Our findings suggest that H3K9me3 regulates neurogenesis in part by silencing the growth-inhibitory gene Cdkn1c in intermediate progenitors. These results underscore the critical role of heterochromatin in the temporal control of neurogenesis.

developmental biology↗

bioRxiv2024

A Vector System Encoding Histone H3 Mutants Facilitates Manipulations of the Neuronal Epigenome

The differentiation of developmental cell lineages is associated with genome-wide modifications in histone H3 methylation. However, the causal role of histone H3 methylation in transcriptional regulation and cell differentiation has been difficult to test in mammals. The experimental overexpression of histone H3 mutants carrying lysine-to-methionine (K-to-M) substitutions has emerged as an alternative tool for inhibiting the endogenous levels of histone H3 methylation at specific lysine residues. Here, we leverage the use of histone K-to-M mutants by creating Enhanced Episomal Vectors that enable the simultaneous depletion of multiple levels of histone H3 lysine 4 (H3K4) or lysine 9 (H3K9) methylation in projection neurons of the mouse cerebral cortex. Our approach also facilitates the simultaneous depletion of H3K9 and H3K27 trimethylation (H3K9me3 and H3K27me3, respectively) in cortical neurons. In addition, we report a tamoxifen-inducible Cre-FLEX system that allows the activation of mutant histones at specific developmental time points or in the adult cortex, leading to the depletion of specific histone marks. The tools presented here can be implemented in other experimental systems, such as human in vitro models, to test the combinatorial role of histone methylations in developmental fate decisions and the maintenance of cell identity.

neuroscience↗

bioRxiv2019

Transcriptional regulation of MGE progenitor proliferation by PRDM16 controls cortical GABAergic interneuron production

The mammalian cortex is populated by neurons derived from neural progenitors located throughout the embryonic telencephalon. Excitatory neurons are derived from progenitors located in the dorsal telencephalon, while inhibitory interneurons are generated by ventral telencephalic progenitors. The transcriptional regulator PRDM16 is expressed by radial glia, neural progenitors present in both regions; however, its mechanisms of action are still not fully understood. It is unclear if PRDM16 functions plays a role in neurogenesis in both dorsal and ventral progenitor lineages, and if so, whether it does so by regulating common or unique networks of genes. Here, we show that Prdm16 expression in MGE progenitors is required for maintaining their proliferative capacity and for the production of proper numbers of pallial GABAergic interneurons. PRDM16 binds to cis-regulatory elements and represses the expression of region-specific neuronal differentiation genes, thereby controlling the timing of neuronal maturation. Our results highlight the importance of PRDM16 for the development of both excitatory and inhibitory cortical circuits. We demonstrate the existence of convergent developmental gene expression programs regulated by PRDM16, which utilize both common and region-specific sets of genes in the cortex and the MGE to control the proliferative capacity of neural progenitors, ensuring the generation of correct numbers of cortical neurons.

neuroscience↗