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Allele-Resolved Single-Cell Multi-Omics Uncovers the Dynamics and Transcriptional Kinetics of X-Chromosome Upregulation

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Allele-Resolved Single-Cell Multi-Omics Uncovers the Dynamics and Transcriptional Kinetics of X-Chromosome Upregulation bioRxiv preprint doi: https://doi.org/10.1101/2021.07.14.452323; this version posted July 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Allele-resolved single-cell multi-omics uncovers the dynamics and transcriptional kinetics of X-chromosome upregulation Antonio Lentini1, Huaitao Cheng2, Joyce C. Noble1, Natali Papanicolaou1, Christos Coucoravas1, Nathanael Andrews2, Qiaolin Deng3, Martin Enge2 and Björn Reinius1* 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 2Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. 3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. *Correspondence to: [email protected] Abstract degradation and gene loss of the Y chromosome where evolution of XCI followed as a second step to avoid the lethal 2 X-chromosome inactivation (XCI) and upregulation (XCU) dose of two hyperactive X alleles in females . This still stands 3,4 are the major opposing chromosome-wide modes of gene as the prevailing evolutionary hypothesis . However, despite regulation that collectively achieve dosage compensation in being central for the regulatory model of dosage mammals, but the regulatory link between the two remains compensation, the developmental sequence of upregulation elusive. Here, we use allele-resolved single-cell RNA-seq and inactivation has remained elusive. The question of XCU combined with chromatin accessibility profiling to finely timing and dynamics is further perplexed as key model 5,6 dissect the separate effects of XCI and XCU on RNA levels species such as rodents experience two waves of XCI which during mouse development. We uncover that balanced X would in theory expose female embryos to a lethal X dosage dosage is flexibly attained through expression tuning by XCU twice. Indeed, while the timeline and molecular mechanisms in a sex- and lineage-specific manner along varying degrees of XCI are well characterized and known to be linked to the 7 of XCI and across developmental and cellular states. Male pluripotency state , the dynamics and regulation of XCU are blastomeres achieve XCU upon zygotic genome activation largely undetermined. Previous studies have approximated while females experience two distinct waves of XCU, upon XCU primarily by relative measurements between non-allelic 8–13 imprinted- and random XCI, and ablation of Xist impedes total expression levels of X and autosomes in steady-state female XCU. Contrary to widely established models of which is convoluted in the presence of confounding allelic mammalian dosage compensation, naïve female embryonic processes, such as XCI. It is therefore unsurprising that cells carrying two active X chromosomes do not exhibit reports on establishment, maintenance, and potential reversal 8,14,15 upregulation but express both alleles at basal level, yet of XCU have been conflicting . Disentangling the collectively exceeding the RNA output of a single hyperactive isolated effects of XCU and XCI is not trivial and would allele. We show, in vivo and in vitro, that XCU is kinetically require quantitative gene expression measurements at cellular driven by X-specific modulation of transcriptional burst and allelic resolution, only recently enabled by allele-resolved frequency, coinciding with increased compartmentalization single-cell RNA-seq (scRNA-seq). Additionally, this requires of the hyperactive allele. Altogether, our data provide careful computational dissection of stochastic allelic unprecedented insights into the dynamics of mammalian processes affecting expression measurements at the cellular 16 XCU, prompting a revised model of the chain in events of level , including the effects of stochastic transcriptional allelic regulation by XCU and XCI in unitedly achieving bursting on allelic expression as well as random XCI (rXCI), stable cellular levels of X-chromosome transcripts. progressing heterogeneously in individual cells. Here, we uncover the XCU dynamics in mouse at cellular and allelic resolution throughout stem cell priming in vitro as well as early embryonic development in vivo. Surprisingly, Introduction our data reveal that XCU is neither a constitutive state of hyper transcription of the X chromosome, nor established as In therian mammals, the X chromosome is present as two a discrete regulatory event, but is a flexible process that copies in females but only one in males. Correct balance of quantitatively tunes RNA synthesis proportionally to the gene dosage is vital for homeostasis and normal cell function, output of the second X allele. We demonstrate sex- and and two major X-chromosome-wide mechanisms ensure lineage-specific initiation and maintenance of XCU in 1 balanced genomic expression . XCU resolves X-to-autosomal conjunction with gene-regulatory events that would otherwise gene-dose imbalances in males by hyperactivation of the X leave expression dosage unbalanced. Finally, building on chromosome whereas XCI silences one X allele in females, these new insights, we provide a revised model of dosage 1 equalizing expression between the sexes . It was first compensation in the early mammalian embryogenesis, proposed in the 1960s that two-fold expression upregulation bridging the allele-specific dynamics of XCU and XCI. through XCU evolved as a first step to compensate for bioRxiv preprint doi: https://doi.org/10.1101/2021.07.14.452323; this version posted July 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Results effects related to the differentiation process. To independently validate these findings, we reanalyzed recently published 3’ Female naïve mESCs do not exhibit X-chromosome UMI-tagged allele-specific scRNA-seq data of 2i withdrawal 21 upregulation in mESCs . Under these conditions, XCI is spontaneously initiated at a considerably lower rate compared to EpiSC 17 Exit from pluripotency in mouse embryonic stem cells priming , allowing us to observe the effect of biallelic versus (mESCs) is accompanied by rXCI in females17. We modelled monoallelic X expression over a wider timespan (Extended this process by differentiating naïve mESCs of mixed genetic Data Fig. 1h). In agreement with our EpiSC priming results, background (C57BL6/J × CAST/EiJ) cultured under 2i we observed that total X-linked expression aggregated across [Gsk3+MEK inhibition] condition towards primed epiblast both alleles was consistently higher in XaXa cells than those stem cells (EpiSCs; Activin A + FGF2) for up to 7 days in undergoing XCI at all timepoints, yet lack of biallelic XCU in vitro, during which single cells were captured (Fig 1a, the XaXa state (Extended Data Fig. 1i-j). Methods). These F1 hybrid cells carry a high density of Our finding that two moderately expressed X alleles parental-origin-specific single-nucleotide polymorphisms achieve a higher total expression dosage than a single which we leveraged using sensitive full-length scRNA-seq hyperactive X allele suggests that XCU does not attain (Smart-seq318) to obtain allelic information across transcripts complete compensation at the transcript-count level (i.e. less and RNA counts by unique molecular identifiers (UMIs) than two-fold upregulation). Indeed, we calculated relative (Extended Data Fig. 1a). After quality filtering, we captured gene-wise expression of the same active allele transitioning allelic expression of up to 576 X-linked and 18,043 autosomal from XaXa into XaXi state (Fig. 1i) which demonstrated a genes in 687 cells, highlighting that our data provided near pronounced shift in X-linked expression yet with fold- -40 genome-wide allelic resolution and the sensitivity to study changes below two (median XC57 = 1.62, PC57 = 1.41 × 10 -48 allelic regulation on the gene-level in single cells. The mESC- and median XCAST = 1.67, PCAST = 5.72 × 10 , Wilcoxon to-EpiSC transition triggered distinct expression changes signed-rank test). While these findings conceptually conflict accompanied by the loss of pluripotency factors (e.g. Sox2 & the assumption that XCI acts on a biallelically hyperactive 3,4 Nanog) and induction of lineage-specific factors (e.g. Fgf5 & XaXa state , the scenario remains compatible with the notion Krt18) together with related pathways (Fig. 1b-c, Extended that expression dosage of two active X alleles blocks or delays 22 Data Fig. 1b-c and Supplementary Table 1), signifying differentiation of female mESCs as the total X dosage is successful stem cell priming. As expected, female naïve reduced when female mESCs transition from naïve to primed mESCs, carrying two active X alleles (XaXa state), pluripotency (XaXa → hyperactive Xa’’Xi state, where ’’ demonstrated an elevated total X-gene expression dosage that denotes increased activity) (Fig. 1j). diminished upon exit from pluripotency (Fig. 1d). This has In summary, our results reveal the important finding that the previously been attributed to the silencing of one out of two two active X alleles in female naïve mESCs lack X- hyperactive X alleles through XCI10. We confirmed the upregulation, whereas hyperactivation of transcription (<2- elevated X dosage in naïve female XX mESCs compared to fold) is present in cellular states with a single active X- both male XY and female XO (Turner syndrome) mESCs in chromosome copy. bulk RNA-seq19,20 (Fig. 1e). At the same
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