Biology subjects

Naik, H. C.

Publications and source records attributed to Naik, H. C..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary origins and chromatin state shape X-chromosome upregulation pattern during eutherian and metatherian embryogenesis

In mammals, silent state of one of the X-chromosomes in female balance the X-dosage between sexes. In parallel, X to autosome imbalance due to monoallelic expression of X-linked genes relative to biallelic autosomal genes, is primarily compensated through the X-chromosome upregulation (XCU). It has been demonstrated that X-chromosome inactivation (XCI) and XCU coincides during embryogenesis, however, XCU is not global and it occurs in a gene-specific manner. The underlying mechanistic aspects of such specificity of XCU remain unknown. Here, we provide systematic and comparative analysis across eutherians (mouse, human and pig) and metatherian (opossum) embryogenesis to determine if evolutionary origins shape the XCU. Intriguingly, we show that while evolutionary older X-linked genes (predating mammalian divergence) undergo robust XCU consistently across developmental stages, younger mammalianLJorigin genes do not. Similarly, the eutherian X-linked genes conserved in metatherian X (X-ortholog) undergo robust XCU, whereas genes orthologus to metatherian autosome (Auto-ortholog) exhibit weaker pattern of XCU. Further, strata-wise comparison revealed that genes in older XLJchromosome strata (1-2) consistently undergo upregulation, whereas strata 3-4 genes do not. Importantly, we show that different evolutionary classes of X-linked genes, which undergo robust XCU, are often enriched with active chromatin marks (H3K36me3, H3K27ac and H3K4me1) relative to the autosome, suggesting that chromatin state mediate the XCU. Moreover, we show that often active-marks enrichment correlates with differential XCU dynamics of different class of genes. Taken together, our study provides significant insight into the evolutionary dynamics of XCU and underlying mechanistic framework.

genetics↗

bioRxiv2024

Single-cell allelic transcriptomic analysis unravels intratumoral gene expression heterogeneity linked to TNBC pathogenesis

Triple-negative breast cancer (TNBC) is the most aggressive subclass of breast cancer, which exhibits high intratumoral heterogeneity. Intratumoral heterogeneity often drives the evolution of drug resistance towards tumour therapy in TNBC. However, the contributing factors and mechanisms behind the intratumoral heterogeneity in TNBC remain poorly understood. It has been implicated that copy number variations (CNVs) often create allelic imbalance and thereby contribute to intratumoral gene expression heterogeneity. However, other processes, such as epigenetic and transcriptional processes, can also contribute to allelic expression heterogeneity in tumour cells. Here, we have investigated how allelic expression heterogeneity contributes to intratumoral heterogeneity in TNBC by performing genome-wide allelic gene expression analysis, excluding most of the CNVs, using single-cell RNA-sequencing datasets. We found widespread monoallelic expression of many genes across different cell types of TNBC. Notably, we found a profound heterogeneity of allelic expression patterns of many genes within TNBC epithelial cells, creating distinct subpopulations of epithelial cells. Importantly, we show that these genes with allelic expression pattern heterogeneity between subpopulations are linked to TNBC immune-surveillance and drug-resistance related pathways, thereby overall shaping the pathogenesis outcomes. Finally, we show that the promoter regions of these genes with profound monoallelic expression are often hypermethylated in TNBC patients. Altogether, our findings reveal that heterogeneous allelic expression patterns contribute to intratumoral heterogeneity and are linked to TNBC pathogenesis.

cancer biology↗

bioRxiv2024

Role of m6A RNA methylation in dosage compensation

In therian mammals, inactivation of one of the X-chromosomes in females balances the dosage of X-linked gene expression between the sexes. On the other hand, upregulation of active-X balances the dosage of monoallelically expressed X-linked genes with biallelic autosomal genes (AA). Factors and mechanisms involved in the maintenance of X-chromosome inactivation (XCI) and X to autosome dosage compensation remain underexplored. Recently, it has been implicated that N6-methyladenosine (m6A) RNA modification contributes to XCI and X to autosome dosage compensation. Here, we have investigated the role of m6A RNA methylation in the maintenance of XCI and X to autosome dosage compensation in early embryonic lineages. Surprisingly, we find that the depletion of m6A RNA methylation does not affect the maintenance of inactive-X gene silencing in mouse epiblast stem cells (EpiSC), trophoblast stem cells (TSC) and extraembryonic endoderm stem cells (XEN). On the other hand, we show that m6A marks are less enriched on X-linked transcripts than the autosomal transcripts in early embryonic lineages. It is believed that less enrichment of m6A in X-linked transcript increases the stability of the X-linked transcript and thereby contributes to the X to autosome dosage compensation. Interestingly, we find that while X-linked transcripts without m6A are fully dosage compensated, transcripts with m6A undergo partial X to autosome dosage compensation in EpiSC, TSC and XEN. However, we find that the depletion of m6A has a minor effect on the X to autosome dosage compensation. Taken together, our study provides significant insight into the role of m6A RNA methylation in dosage compensation of early embryonic lineages.

genetics↗

bioRxiv2020

Transcriptional bursting shape autosomal dynamic random monoallelic expression inpre-gastrulation embryos

In recent years, allele-specific single-cell RNA-seq (scRNA-seq) analysis has demonstrated wide-spread dynamic random monoallelic expression of autosomal genes (aRME) in different cell types. However, the prevalence of dynamic aRME during pre-gastrulation development remains unknown. Here, we show that dynamic aRME is wide-spread in different lineages of pre-gastrulation embryos. Additionally, the origin of dynamic aRME remains poorly understood. Theoretically, it is believed that independent transcriptional bursting from each allele leads to the dynamic aRME. However, based on analysis of allele-specific burst kinetics of autosomal genes, we found that allelic burst is not perfectly independent, rather it happens in semi-coordinated fashion. Importantly, we show that semi-coordinated allelic bursting of the genes; particularly with low burst frequency, leads to frequent asynchronous allelic bursting, thereby shaping the landscape of dynamic aRME in pre-gastrulation embryos. Altogether, our study provides significant insight into the prevalence and origin of dynamic aRME and cell to cell expression heterogeneity during early mammalian development. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genetics↗