Biology subjects

Talukdar, M.

Publications and source records attributed to Talukdar, M..

5 recordsLinked to original sources

bioRxiv2025

Autism-Associated Genes and Neighboring lncRNAs Converge on Key Gene Regulatory Networks

Autism spectrum disorder (ASD) is highly heritable, and mutations in hundreds of genes have been implicated as individually rare causes of ASD1-3. Understanding how disruptions to these functionally diverse genes lead to the core features of ASD remains a major challenge4. Moreover, ASD is three- to four-fold more common in males than females5, and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males6,7, but the biological basis of this "female protective effect" (FPE) is unknown8,9. Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST, that drive this transcriptomic convergence. Furthermore, the X-linked transcription factor ZFX, which is expressed from both the active and the inactive X chromosomes in females10, emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.

genetics↗

bioRxiv2024

Cell-type-informed genotyping of mosaic focal epilepsies reveals cell-autonomous and non-cell-autonomous disease-associated transcriptional programs

Recent studies demonstrate growing roles for genetic mosaicism in neurodevelopmental and neuropsychiatric disorders, with the paradigm being drug-resistant pediatric focal epilepsy related to activating somatic variants in the PI3K-mTOR pathway. While identifying the genotype-associated changes at the single-cell level is fundamental to understanding disease pathophysiology, this remains technically challenging in human tissue samples with existing methods. Here, we performed single-nucleus RNA-sequencing (snRNA-seq) of 20 focal cortical dysplasia (FCD) samples removed surgically for treatment of drug-resistant epilepsy, and 10 non-FCD controls, and we developed a new approach, Genotyping Of Transcriptomes Enhanced with Nanopore sequencing (GO-TEN), that combines targeted complementary (c)DNA sequencing with snRNA-seq to perform concurrent single-nucleus genotyping and transcriptional analysis. We find that mosaic pathogenic variants in FCD do not produce a detectable novel cell identity, but instead we observe conserved cell types present both in FCD cases and non-FCD control specimens. Similarly, GO-TEN analysis shows that most pathogenic variant-carrying cells have well-differentiated neuronal or glial identities and are enriched for layer II-III excitatory neurons. We identify cell-intrinsic disruption of glutamate and GABA-A signaling pathways in variant-carrying neurons and altered intercellular signaling, making potential mechanisms for epileptogenesis in FCD. In summary, by addressing genotype-specific changes in mosaic epilepsy-associated lesions, our study highlights new potential disease mechanisms and therapeutic targets.

genetics↗

bioRxiv2024

Genes of the fatty acid oxidation pathway are upregulated in female as compared to male cardiomyocytes

Human females and males differ in cardiac physiology and pathology, even after controlling for sex differences in anthropometrics, lifestyle, and environment. For example, females and males differ in cardiac stroke volume and ventricular thickness, and they exhibit different rates and symptoms of cardiovascular disease. Less is understood about molecular differences in female and male hearts, such as sex differences in gene expression. Here we present an integrative framework utilizing bulk and single-nucleus RNA-sequencing data to study sex differences in the cardiac transcriptome. We show that genes of the fatty acid oxidation (FAO) pathway, the primary source of energy in the heart, are expressed more highly in healthy female than in healthy male hearts. We demonstrate that this sex difference is due to cardiomyocyte-specific, female-biased expression of FAO genes and cannot be explained by sex differences in cardiac cellular composition or number of mitochondria, where FAO takes place. Finally, we observe increased cardiac flux and energetic utilization of free fatty acids in female compared to male hearts. Overall, our results demonstrate that male and female human hearts exhibit fundamental differences in metabolism that likely contribute to sex differences in cardiac physiology and pathology.

genomics↗

bioRxiv2024

Somatic cancer driver mutations are enriched and associated with inflammatory states in Alzheimer's disease microglia

Alzheimers disease (AD) is an age-associated neurodegenerative disorder characterized by progressive neuronal loss and pathological accumulation of the misfolded proteins amyloid-{beta} and tau1,2. Neuroinflammation mediated by microglia and brain-resident macrophages plays a crucial role in AD pathogenesis1-5, though the mechanisms by which age, genes, and other risk factors interact remain largely unknown. Somatic mutations accumulate with age and lead to clonal expansion of many cell types, contributing to cancer and many non-cancer diseases6,7. Here we studied somatic mutation in normal aged and AD brains by three orthogonal methods and in three independent AD cohorts. Analysis of bulk RNA sequencing data from 866 samples from different brain regions revealed significantly higher ([~]two-fold) overall burdens of somatic single-nucleotide variants (sSNVs) in AD brains compared to age-matched controls. Molecular-barcoded deep (>1000X) gene panel sequencing of 311 prefrontal cortex samples showed enrichment of sSNVs and somatic insertions and deletions (sIndels) in cancer driver genes in AD brain compared to control, with recurrent, and often multiple, mutations in genes implicated in clonal hematopoiesis (CH)8,9. Pathogenic sSNVs were enriched in CSF1R+ microglia of AD brains, and the high proportion of microglia (up to 40%) carrying some sSNVs in cancer driver genes suggests mutation-driven microglial clonal expansion (MiCE). Analysis of single-nucleus RNA sequencing (snRNAseq) from temporal neocortex of 62 additional AD cases and controls exhibited nominally increased mosaic chromosomal alterations (mCAs) associated with CH10,11. Microglia carrying mCA showed upregulated pro-inflammatory genes, resembling the transcriptomic features of disease-associated microglia (DAM) in AD. Our results suggest that somatic driver mutations in microglia are common with normal aging but further enriched in AD brain, driving MiCE with inflammatory and DAM signatures. Our findings provide the first insights into microglial clonal dynamics in AD and identify potential new approaches to AD diagnosis and therapy.

genomics↗

bioRxiv2022

Glial dysregulation in human brain in Fragile X-related disorders

AbstractWhile large trinucleotide repeat expansions at the FMR1 locus cause Fragile X Syndrome (FXS), smaller "premutations" are associated with the late-onset condition Fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features, with no clear molecular explanation for these marked differences. One prevailing theory posits that the premutation uniquely causes neurotoxic increases in FMR1 mRNA (i.e., 4-8-fold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single- nucleus RNA-sequencing to post-mortem frontal cortex and cerebellum from 9 individuals with Fragile X mutations as well as age and sex matched controls (n=6) to assess cell-type specific molecular neuropathology. We found robust reduction of FMR1 mRNA in FXS as expected, with modest but significant upregulation ([~]1.3 fold) of FMR1 in glial clusters associated with premutation expansions. In premutation cases we identified alterations in glia number in cortex and cerebellum. Differential expression analysis demonstrated altered cortical oligodendrocyte development, while gene ontology analysis revealed alterations in neuroregulatory roles of glia, such as glial modulation of neurotransmission and synaptic structure. We identified significant enrichment of known FMR1 protein target genes in differentially expressed gene lists in FXS as well as the premutation, suggesting FMR1 protein target pathways may represent a shared source of dysfunction in both conditions despite opposite FMR1 mRNA changes. These findings challenge existing dogma regarding FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing novel therapeutic targets directly derived from the human condition.

neuroscience↗