Biology subjects

Nazim, M.

Publications and source records attributed to Nazim, M..

4 recordsLinked to original sources

bioRxiv2025

Cell-Type-Resolved Isoform Atlas of Human Tissues Reveals Age and Alzheimer's Disease-Associated Splicing Changes

Alternative splicing is a key mechanism for transcriptomic diversity, but how isoforms map to specific cell types in bulk tissues remains unclear. We present Sciege, a multimodal method that integrates bulk short-read RNA-seq with single-cell and long-read data to estimate cell type-specific isoform distributions. Through simulations, we demonstrate that Sciege accurately estimates isoform abundances and identifies differentially abundant transcripts through statistical tests. Applied to seven tissues in GTEx and brain tissue in ROSMAP datasets, Sciege generates a first-to-date multi-tissue isoform atlas and reveals isoform changes linked to cell types, aging, and Alzheimers disease. Validation with external cohorts and experimental data confirms our findings. Notably, we identify upregulation of the MAPT-010 isoform in AD inhibitory neurons, consistent with known methylation signatures. Our approach demonstrates the value of integrating RNA-seq data to study cell type-specific splicing and provides a foundation for further genetic and functional studies of alternative splicing across biological contexts.

bioinformatics↗

bioRxiv2025

Gene Specific Pathogenicity Predictor for Chromatin-Remodeling BAF Complex-Associated Neurodevelopmental Disorders

Advancements in whole genome sequencing have increased the number of variants of uncertain significance (VUS) identified in patient genomes. This has created a diagnostic bottleneck for genetic counselors tasked with sifting through these variants and determining those most likely to be causative for a patients clinical presentation. Machine learning (ML) tools can aid in identifying pathogenic variants from VUS, but there is a need for gene-specific algorithms that predict pathogenic variants with high accuracy. To address this need, we present a workflow for developing gene-specific, ensemble-learning ML tools, that leverage outputs from other algorithms, locations of variants within the gene, and evolutionary conservation data to make a prediction of pathogenicity. Variants in SMARCA2 and SMARCA4 that are associated with rare neurodevelopmental diseases were used to screen 15 ML algorithms. A random forest learner was tuned to yield a final accuracy of 0.93 on holdout data. Generalizing this predictor to other BAF complex proteins resulted in a sharp decline in performance. We trained a final predictor for all genes in the study to create a predictor that identifies pathogenic variants in these BAF subunits with an accuracy of 0.91 on holdout data. This predictor specific to BAF complex proteins performs with higher accuracy and AUROC than any other predictor. The decline in performance when generalized to other proteins emphasizes the need for the gene-specific calibration of predictors. Our workflow for the development of such models provides a quick, computationally inexpensive route for improving the ML tools available to genetic counselors. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/675179v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1cd55fcorg.highwire.dtl.DTLVardef@1c81d8corg.highwire.dtl.DTLVardef@10bd965org.highwire.dtl.DTLVardef@ed9d67_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

bioinformatics↗

bioRxiv2024

The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons.

Synaptic function is modulated by local translation of mRNAs that are transported to distal portions of axons and dendrites. The Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is broadly expressed across cell types, almost exclusively as a nuclear non-coding RNA. We found that in differentiating neurons, a portion of Malat1 RNA redistributes to the cytoplasm. Depletion of Malat1 from neurons stimulated expression of particular pre- and post-synaptic proteins, implicating Malat1 in their regulation. Neuronal Malat1 is localized to both axons and dendrites in puncta that co-stain with Staufen1 protein, similar to neuronal granules formed by locally translated mRNAs. Ribosome profiling of mouse cortical neurons identified ribosome footprints within a region of Malat1 containing short open reading frames. The upstream-most reading frame (M1) of the Malat1 locus was linked to the GFP coding sequence in mouse ES cells. When these gene-edited cells were differentiated into glutamatergic neurons, the M1-GFP fusion protein was expressed. Antibody staining for the M1 peptide confirmed its presence in wildtype neurons, and showed enhancement of M1 expression after synaptic stimulation with KCL. Our results indicate that Malat1 serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.

molecular biology↗

bioRxiv2023

Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation

Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) alters splicing of DPF2, a subunit of BAF chromatin remodeling complexes. Dpf2 exon 7 is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 splicing, resulting in a longer DPF2-L isoform. Gene expression changes are induced by DPF2-L in ESC, and by DPF2-S in neurons. In ESC, chromatin immunoprecipitation locates DPF2-S but not DPF2-L at sites bound by pluripotency transcription factors. In neuronal progenitors, DPF2-S sites coincide with NFI protein binding, and DPF2-L sites with CTCF. DPF2-S sites show enhancer chromatin modifications, while DPF2-L sites show modifications associated with promoters. In sum, alternative splicing events during neuronal development impact chromatin organization by altering BAF complex targeting.

molecular biology↗