Biology subjects

Dionne, O.

Publications and source records attributed to Dionne, O..

2 recordsLinked to original sources

bioRxiv2025

The Fragile X mental retardation protein (FMRP) coordinates an epigenetic checkpoint in neural progenitor cells

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which encodes the multifunctional RNA-binding protein FMRP. While FMRP is best known for its roles in RNA metabolism, it can also associate with chromatin through recognition of histone H3 lysine 79 di-methylation (H3K79me2), an epigenetic mark linked to transcriptionally active genes. However, the functional relevance of this FMRP-H3K79me2 interaction has remained largely unexplored in the context of FXS pathophysiology. We assessed H3K79me2 levels during the differentiation of induced pluripotent stem cells (iPSCs) generated from both healthy individuals and FXS patients and discovered a global increase in H3K79me2 levels specifically in FXS neural progenitor cells (NPCs). Altered H3K79me2 landscape drives widespread transcriptional dysregulation, characterized by reduced expression of neurogenesis-associated genes alongside aberrant activation of programs promoting proliferation and glial lineage commitment. Functionally, these changes result in enhanced NPCs proliferation and a biased differentiation trajectory. Notably, pharmacological reduction of global H3K79me2 levels in FXS NPCs using DOT1L inhibitors effectively mitigates these defects, restoring proliferation rate and rebalancing lineage specification, thereby rescuing key aspects of the pathological phenotype. Collectively, our findings identify an H3K79me2-dependent epigenetic barrier regulating NPC proliferation and lineage commitment and link its dysregulation to the neurodevelopmental defects associated with FXS.

neuroscience↗

bioRxiv2023

A neuron-specific microexon ablates the novel DNA-binding function of a histone H3K4me0 reader PHF21A

How cell-type-specific chromatin landscapes emerge and progress during metazoan ontogenesis remains an important question. Transcription factors are expressed in a cell-type-specific manner and recruit chromatin-regulatory machinery to specific genomic loci. In contrast, chromatin-regulatory proteins are expressed broadly and are assumed to exert the same intrinsic function across cell types. However, human genetics studies have revealed an unexpected vulnerability of neurodevelopment to chromatin factor mutations with unknown mechanisms. Here, we report that 14 chromatin regulators undergo evolutionary-conserved neuron-specific splicing events involving microexons. Of the 14 chromatin regulators, two are integral components of a histone H3K4 demethylase complex; the catalytic subunit LSD1 and an H3K4me0-reader protein PHF21A adopt neuron-specific forms. We found that canonical PHF21A (PHF21A-c) binds to DNA by AT-hook motif, and the neuronal counterpart PHF21A-n lacks this DNA-binding function yet maintains H3K4me0 recognition intact. In-vitro reconstitution of the canonical and neuronal PHF21A-LSD1 complexes identified the neuronal complex as a hypomorphic H3K4 demethylating machinery with reduced nucleosome engagement. Furthermore, an autism-associated PHF21A missense mutation, 1285 G>A, at the last nucleotide of the common exon immediately upstream of the neuronal microexon led to impaired splicing of PHF21A-n. Thus, ubiquitous chromatin regulatory complexes exert unique intrinsic functions in neurons via alternative splicing of their subunits and potentially contribute to faithful human brain development.

molecular biology↗