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@PHDTHESIS{Panten:295846,
      author       = {J. Panten$^*$},
      title        = {{C}auses and consequences of context-specific allelic
                      imbalance},
      school       = {Universität Heidelberg},
      type         = {Dissertation},
      reportid     = {DKFZ-2024-02663},
      year         = {2024},
      note         = {Dissertation, Universität Heidelberg, 2024},
      abstract     = {Gene expression has to be regulated in a cell type-specific
                      manner to ensure proper functionality of cell types and
                      tissues. In a diploid organism, the two alleles of a gene
                      can be regulated independently, causing differential
                      contribution to mRNA levels and thus to cellular function.
                      Allelic imbalance in gene expression has long been
                      recognized as a contributor to cellular phenotypes, however,
                      it is not well understood how and to which extent allelic
                      imbalance is shaped by the regulatory environment of
                      different cell types. Recent advances in single-cell
                      technologies provide the opportunity to profile gene
                      expression and its regulation in a cell type-specific manner
                      at scale, extending our understanding of genome function. In
                      this thesis, I performed a comprehensive analysis of
                      allele-specific expression (ASE) at single-cell resolution
                      in interspecific mouse hybrids. I first analysed the
                      differentiation-dependence of allelic imbalance caused by
                      strain-specific genetic effects during murine
                      spermatogenesis. This analysis shows that across cell types,
                      variation in ASE is extremely pervasive. Using an F1 trio
                      design, I further separated cis- and trans-contributions to
                      gene expression divergence and showed that cell
                      type-specific action of regulatory variants is mainly driven
                      by the interaction of cis-effects with the cellular
                      environment. Finally, I investigated the contribution of
                      dynamic genetic effects to cell type-specific
                      transcriptional evolution. Next, I focussed on ASE caused by
                      an epigenetic mechanism, namely X-chromosome inactivation
                      (XCI). In female humans and mice, XCI causes mosaic
                      haplotype-specific expression of X-linked genes, and escape
                      from XCI can lead to increased gene dosage compared to
                      males. Using single-cell genomics assays, I developed an
                      analysis approach to distinguish active and inactive
                      X-chromosomes in individual cells, which allowed me to
                      identify cell type-specific escape. I further showed that
                      T-cell expansion during ageing leads to globally impaired
                      silencing of the inactive X which is associated with an
                      exhaustion phenotype. These findings replicated on the level
                      of chromatin accessibility, demonstrating that variation in
                      escape is associated with an active chromatin state.
                      Collectively, I showed that escape can vary at the cell type
                      level and during organismal ageing. While these results show
                      that escape from XCI is plastic, they do not address how it
                      might be regulated in different cell types. In the final
                      chapter, I therefore explored whether the Xist long
                      non-coding RNA can regulate escapee expression. Using
                      allele-specific RNA-Seq data, I showed that increased
                      Xist-levels lead to almost complete silencing of escapees in
                      neural progenitor cells. Modelling of silencing trajectories
                      showed substantial variability among genes in both their
                      resistance to silencing as well as their reversibility,
                      suggesting that escape is genomically encoded. Finally, I
                      demonstrated that over-expression of Xist leads to escapee
                      silencing in early embryogenesis. These results provide a
                      potential mechanism that might drive variability in
                      expression from the inactive X. Taken together, this thesis
                      delineates to which extent allelic imbalance is driven by
                      cell typespecific regulatory environments and suggests
                      analysis approaches for allele-resolved single-cell data.
                      This provides the basis for a comprehensive survey of
                      allelic usage in vivo and the molecular mechanisms causing
                      its context-specificity.},
      cin          = {B260 / B270},
      cid          = {I:(DE-He78)B260-20160331 / I:(DE-He78)B270-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)11},
      url          = {https://inrepo02.dkfz.de/record/295846},
}