Biology subjects

Chandel, D.

Publications and source records attributed to Chandel, D..

4 recordsLinked to original sources

bioRxiv2021

Single cell analysis reveals X chromosome upregulation is not global and primarily belongs to ancestral genes in pre-gastrulation embryos

Evolution of sex chromosome dosage compensation in mammals remains poorly understood. Ohnos hypothesis state that evolution of dosage compensation occurred through two steps: first, to compensate the dosage imbalance created due to the degradation of Y chromosome in male, upregulation of X-chromosome happened. Subsequently, transmission of X-chromosome upregulation (XCU) in female led to the evolution of X-chromosome inactivation (XCI) to counteract extra dosage of X-linked genes in female cells. Here, we have profiled gene-wise dynamics of XCU in pre-gastrulation mouse embryos at single cell level and found that XCU is dynamically linked with XCI, however, XCU is not global or chromosome-wide like XCI. Therefore, our result raises question whether XCU driven the evolution of XCI. If so, then why XCI is chromosome wide while XCU is not. We propose that XCI might have evolved independent of XCU and therefore refining the current model is necessary. Separately, we show that higher occupancy of different activating factors at upregulated X-linked genes leads to enhanced transcriptional burst frequency and thereby leads to upregulation. On the other hand, our analysis indicates that extent of upregulation, enrichment of different activating marks differs between ancestral and newly acquired X-linked genes. Altogether, our study provides significant insight into the dynamics and mechanistic basis of evolution of sex chromosome dosage compensation. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

genetics↗

bioRxiv2020

Dynamic erasure of X chromosome upregulation during iPSC reprogramming and in the inner cell mass

In mammals, sex chromosome dosage is compensated through X-chromosome inactivation and active-X upregulation. It is believed that during early development, X-chromosome inactivation and active X upregulation happen in a highly coordinated fashion. However, such coordination between two X-chromosomes in other developmental contexts remains unexplored. Here, we have profiled the coordination between two X-chromosomes in female cells in different developmental contexts and cell types: pre-implantation embryos, embryonic epiblast cells, iPSC reprogramming, germ cell reprogramming, B-cell, and extra-embryonic endoderm stem (XEN) cells. Interestingly, we found that two X-chromosomes in female cells are not always coordinated; instead, it happens in a lineage-specific manner. Specially, while embryonic mouse epiblast cells, iPSC undergo erasure of X-upregulation upon reactivation of the inactive X, germ cells do not. Importantly, we show that the erasure of X-upregulation in epiblast or iPSC is potentially mediated via undifferentiated embryonic transcription Factor 1 (UTF1), which is absent or lowly expressed in late germ cells and therefore, germ cells are unable to erase upregulation. Moreover, we found that partial reactivation of the inactive X is insufficient to drive the erasure of upregulation globally, nor from their counterparts on the active X in XEN and B-cells. Finally, through a phenomenological mathematical model, we show that cross-inhibition between two X-chromosomes can reproduce the dynamics of reactivation and erasure of upregulation. Altogether, our study provides insight into the coordination between two X-chromosomes in female cells in different developmental contexts and related mechanistic aspects. O_FIG O_LINKSMALLFIG WIDTH=117 HEIGHT=200 SRC="FIGDIR/small/424181v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1f01b7borg.highwire.dtl.DTLVardef@9c586borg.highwire.dtl.DTLVardef@70f8eaorg.highwire.dtl.DTLVardef@e5d000_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗

bioRxiv2019

Single Cell Analysis Reveals Partial Reactivation of X-chromosome Instead of chromosome wide dampening in Naive Human Pluripotent Stem Cells

Recently, a unique form of X-chromosome dosage compensation has been demonstrated in human preimplantation embryos, which happens through the dampening of X-linked gene expression from both X-chromosomes. Subsequently, X-chromosome dampening has also been demonstrated in female human pluripotent stem cells (hPSCs) during the transition from primed to naive state. However, the existence of dampened X-chromosomes remains controversial in both embryos and hPSCs. Specifically, in preimplantation embryos it has been shown that there is inactivation of X-chromosome instead of dampening. Here, we have performed allelic analysis of X-linked genes at the single cell level in hPSCs and found that there is partial reactivation of the inactive X-chromosome instead of chromosome-wide dampening upon conversion from primed to naive state. In addition, our analysis suggests that the reduced X-linked gene expression in naive hPSCs might be the consequence of erasure of active X-chromosome upregulation.

genetics↗