Biology subjects

Aljazi, M. B.

Publications and source records attributed to Aljazi, M. B..

5 recordsLinked to original sources

bioRxiv2022

Neural hyperactivity is a core pathophysiological change induced by deletion of an autism risk gene Ash1l in the mouse brain

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Previous genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). Recent studies demonstrate that loss of Ash1l in the mouse brain is sufficient to induce ASD/ID-like behavioral and cognitive memory deficits, suggesting that disruptive ASH1L mutations are likely to be the causative driver leading to the ASD/ID pathogenesis in human patients. However, the brain pathophysiological changes underlying the Ash1l-deletion-induced ASD/ID-like behavioral and memory deficits remain unknown. Here we show loss of Ash1l in the mouse brain causes locomotor hyperactivity and higher metabolic rates . In addition, the mutant mice display lower thresholds for the convulsant reagent-induced epilepsy and increased neuronal activities in broad brain areas. Thus, our current study reveals that neural hyperactivity is a core pathophysiological change in the Ash1l-deficient mouse brain, which provides a brain-level basis for further studying the cellular and molecular mechanisms underlying the Ash1l-deletion-induced ASD/ID pathogenesis.

neuroscience↗

bioRxiv2021

Impaired KDM2B-mediated PRC1 recruitment to chromatin causes neural stem cell senescence and ASD/ID-like behavioral deficits

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various genetic mutations. Recent clinical studies report that chromosomal 12q24.31 microdeletions are associated with human ASD/ID. However, the causality and underlying mechanisms linking 12q24.31 microdeletions to ASD/ID pathogenesis remain undetermined. Here we show Kdm2b, one of the genes located in chromosomal 12q24.31, plays a critical role in maintaining neural stem cells (NSCs) in the developing mouse brain. Loss of the CxxC-ZF domain of KDM2B impairs its function in recruiting Polycomb repressive complex 1 (PRC1) to chromatin, resulting in de-repression of genes involved in cell apoptosis, cell cycle arrest, NSC premature senescence, and leading to the loss of NSC populations in the brain. Importantly, the Kdm2b mutation is sufficient to induce ASD/ID-like social and memory deficits in adult mice. Thus, our study reveals a critical role of an epigenetic factor KDM2B in normal brain development, a causality between the Kdm2b mutation and genesis of ASD/ID-like phenotypes in mice, and potential molecular mechanisms linking the function of KDM2B-PRC1 in transcriptional regulation and NSC senescence to the12q24.31 microdeletion-associated ASD/ID.

neuroscience↗

bioRxiv2021

Histone H3K36me2-specific methyltransferase ASH1L is required for the MLL-AF9-induced leukemogenesis

ASH1L and MLL1 are two histone methyltransferases that facilitate transcriptional activation during normal development. However, the roles of ASH1L and its enzymatic activity in the development of MLL-rearranged leukemias are not fully elucidated in the Ash1L gene knockout animal models. In this study, we used an Ash1L conditional knockout mouse model to show that loss of ASH1L in hematopoietic progenitor cells impaired the initiation of MLL-AF9-induced leukemic transformation in vitro. Furthermore, genetic deletion of ASH1L in the MLL-AF9-transformed cells impaired the maintenance of leukemic cells in vitro and largely blocked the leukemia progression in vivo. Importantly, the loss of ASH1L function in the Ash1L-deleted cells could be rescued by wild-type but not the catalytic-dead mutant ASH1L, suggesting the enzymatic activity of ASH1L was required for its function in promoting MLL-AF9-induced leukemic transformation. At the molecular level, ASH1L enhanced the MLL-AF9 target gene expression by directly binding to the gene promoters and modifying the local histone H3K36me2 levels. Thus, our study revealed the critical functions of ASH1L in promoting the MLL-AF9-induced leukemogenesis, which provides a molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-arranged leukemias.

cancer biology↗

bioRxiv2020

Loss of ASH1L in developing brains causes autistic-like behaviors in a mouse model

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causal link between ASH1L mutations and ASD/ID remains undetermined. Here we show loss of ASH1L in developing mouse brains is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes a new ASD/ID mouse model revealing the critical function of ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

neuroscience↗

bioRxiv2019

FGF/MAPK signaling pathway regulates the genome-wide occupancy of Polycomb Repressive Complex 2 in murine embryonic stem cells

The recruitment of Polycomb repressive complex 2 (PRC2) to gene promoters is critical for its function in repressing gene expression in murine embryonic stem cells (mESCs). However, previous studies have demonstrated although the expression of early lineage-specific genes is largely repressed, the genome-wide PRC2 occupancy is unexpectedly reduced in naive mESCs. In this study, we provide evidence to show the FGF/ERK signaling determines the global PRC2 occupancy through regulating the expression of PRC2-recruting factor JARID2 in naive mESCs. At the transcriptional level, the de-repression of bivalent genes is predominantly determined by the presence of cell signaling-associated transcription factors but not the status of PRC2 occupancy at gene promoters. Hence, this study not only reveals a key molecular mechanism by which the FGF/ERK signaling in regulating the PRC2 occupancy in mESCs, but also elucidates a fundamental question regarding the functional roles of transcription factors and Polycomb-mediated epigenetic mechanisms in transcriptional regulation.

genetics↗