Biology subjects

Jahani-Asl, A.

Publications and source records attributed to Jahani-Asl, A..

5 recordsLinked to original sources

bioRxiv2026

TCF4 Mediates PHF6 Transcriptional Regulation of Neural Stem Cells in the Developing Brain, a Mechanism Disrupted in Börjeson Forssman Lehmann Syndrome (BFLS)

Transcriptional hierarchies govern neural stem cell (NSC) fate decisions during neurodevelopment, and disruption of these regulatory networks underlies neurodevelopmental disorders. Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability (XLID) caused by mutations in a chromatin-associated transcriptional regulator, the plant homeodomain zinc finger protein 6 (PHF6). Although BFLS mouse models harboring PHF6 patient mutations recapitulate neurogenic and cognitive deficits, the molecular mechanisms linking PHF6 dysfunction to these phenotypes remain poorly understood. Here, we identify transcription factor 4 (TCF4), a basic helix-loop-helix transcription factor implicated in neurodevelopmental and psychiatric disorders, as a critical downstream effector of PHF6 in NSC fate regulation. Tcf4 expression is reduced in BFLS mouse models harbouring R342X and C99F-m mutations and in a conditional Phf6 knockout driven by Nestin-Cre. Mechanistically, PHF6 binds the Tcf4 gene regulatory element upstream of its transcriptional start site (TSS) and promotes Tcf4 expression. Tcf4 depletion in embryonic NSCs enhances self-renewal and stemness, increasing neurosphere formation and expression of stem cell markers, Nestin and Sox2. Conversely, TCF4 restoration rescues NSC defects caused by PHF6 loss of function in BFLS and Phf6/Nestin-Cre mice. This regulatory relationship persists in adult NSCs where TCF4 similarly restricts stem cell expansion. Importantly, restoration of TCF4 expression in embryonic brain ameliorates behavioral and cognitive deficits in BFLS mice. Together, these findings establish a PHF6-Tcf4 transcriptional pathway that restricts NSC self-renewal and links disrupted transcriptional control of NSC fate to the neurodevelopmental and behavioral abnormalities of BFLS.

neuroscience↗

bioRxiv2026

A Multiomic Analysis of Cachectic Mice Reveals Cancer Driven Suppression of Muscle Stem Cell Differentiation

Cancer cachexia affects a large proportion of cancer patients, inducing a rapid decline in muscle mass. Patients with cachexia have a worse prognosis and are less responsive to cancer therapies. The exact cause of cachexia remains unknown, nor are there any effective treatments for the condition. In this study, we use the C26 adenocarcinoma cell line to determine how cancer cells affect myofiber and muscle stem cell function. We determined that C26 cancer cells adapt to the host environment, in both male and female mice, greatly altering their transcriptome to promote their survival and growth. C26 cells directly communicate with muscle stem cells via GDF15 and MMP9. These circulatory factors cause the muscle stem cells to upregulate the EMT pathway and become less capable of undergoing differentiation and contributing to muscle regeneration. Muscle stem cells from tumor bearing mice are less proliferative and less prone to differentiation, Chromatin accessibility data shows that there are fewer accessible myogenic regulatory binding sites. Cytokine array determined that circulating GDF15 and MMP9 were highly upregulated and were derived form C26 tumor cells. However, blocking tumor derived GDF15 is not sufficient to prevent the onset of cachexia and rescue the loss of muscle stem cell function. Together, these findings establish a new conceptual paradigm in which cancer orchestrates muscle wasting through coordinated transcriptional, metabolic, and epigenetic suppression of muscle stem cell differentiation.

cell biology↗

bioRxiv2021

Transcriptional Reprogramming of Skeletal Muscle Stem Cells by the Niche Environment

Adult stem cells are indispensable for tissue regeneration. Tissue-specific stem cells reside in a specialized location called their niche, where they are in constant cross talk with neighboring niche cells and circulatory signals from their environment. Aging has a detrimental effect on the number and the regenerative function of various stem cells. However, whether the loss of stem cell function is a cause or consequence of their aging niche is unclear. Using skeletal muscle stem cells (MuSCs) as a model, we decouple cell-intrinsic from niche-mediated extrinsic effects of aging on their transcriptome. By combining in vivo MuSC heterochronic transplantation models and computational methods, we show that on a genome-wide scale, age-related altered genes fall into two distinct categories regarding their response to the niche environment. Genes that are inelastic in their response to the niche exhibit altered chromatin accessibility and are associated with differentially methylated regions (DMRs) between young and aged cells. On the other hand, genes that are restorable by niche exposure exhibit altered transcriptome but show no change in chromatin accessibility or DMRs. Taken together, our data suggest that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs, and exposure to a young niche can reverse approximately half of all age-associated changes that are not epigenetically encoded. The muscle niche therefore serves as an important therapeutic venue to mitigate the negative consequence of aging on tissue regeneration.

genetics↗

bioRxiv2021

Transcriptional Control of Brain Tumour Stem Cell Fate by a Carbohydrate Binding Protein

Brain tumour stem cells (BTSCs) and intratumoural heterogeneity represent major challenges in glioblastoma therapy. Here, we report that the LGALS1 gene, encoding the carbohydrate binding protein, galectin1, is a key regulator of BTSCs and glioblastoma resistance to therapy. Genetic deletion of LGALS1 alters BTSC gene expression profiles and results in downregulation of gene sets associated with mesenchymal subtype of glioblastoma. Using a combination of pharmacological and genetic approaches, we establish that inhibition of LGALS1 signalling in BTSCs impairs self-renewal, suppresses tumourigenesis, prolongs lifespan, and improves glioblastoma response to ionizing radiation in preclinical animal models. Mechanistically, we show that LGALS1 is a direct transcriptional target of STAT3 with its expression robustly regulated by the ligand OSM. Importantly, we establish that galectin1 forms a complex with the transcription factor HOXA5 to reprogram BTSC transcriptional landscape. Our data unravel an oncogenic signalling pathway by which galectin1/HOXA5 complex maintains BTSCs and promotes glioblastoma.

cancer biology↗

bioRxiv2019

Myf6/MRF4 is a Myogenic Niche Regulator Required for the Maintenance of the Muscle Stem Cell Pool

In metazoans, skeletal muscle evolved to contract and produce force. However, recent experimental evidence suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins, including ligands for downstream activation of key signaling pathways such as EGFR, STAT3 and VEGFR. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce key myokines such as EGF, VEGFA and LIF. Consequently, although Myf6 knockout mice are born with a normal muscle stem cell compartment, they undergo progressive reduction in their stem cell pool during postnatal life. Mechanistically, muscle stem cells from the Myf6 knockout animals show defects in activation of EGFR and STAT3 signaling, upregulate the p38 MAP kinase pathway and spontaneously break from quiescence. Exogenous application of recombinant EGF and LIF rescue the defects in the muscle stem cell pool of Myf6 knockout animals. Finally, skeletal muscles of mice lacking Myf6 have a significantly reduced ability to sustain donor-engrafted muscle stem cells. Taken together, our data uncovers a novel role for Myf6 in regulating the expression of niche factors and myokines to maintain the skeletal muscle stem cell pool in adult mice.

genetics↗