Biology subjects

Zaugg, J. B.

Publications and source records attributed to Zaugg, J. B..

3 recordsLinked to original sources

bioRxiv2020

APOBEC2 binds Chromatin and Represses Transcription during Myoblast Differentiation

The activation induced cytidine deaminase/apolipoprotein B editing complex (AID/APOBEC) family comprises several nucleic acid editors with roles ranging from antibody diversification to mRNA editing. APOBEC2, an evolutionarily conserved member of this family, has neither an established substrate nor a mechanism of action, however genetic evidence suggests functional relevance in tissues such as muscle. Here, we demonstrate that in muscle, APOBEC2 does not have any of the attributed molecular functions of the AID/APOBEC family, such as RNA editing, DNA demethylation, or DNA mutation. Instead, we show that APOBEC2 occupies chromatin at promoter regions of certain genes, whose expression is repressed during muscle cell differentiation. We further demonstrate that APOBEC2 on one hand binds promoter region DNA directly and in a sequence specific fashion, while on the other it interacts with HDAC transcriptional corepressor complexes. Therefore, APOBEC2, by actively repressing the expression of non-myogenesis pathway genes, plays a key role in enforcing the proper establishment of muscle cell fate.

molecular biology↗

bioRxiv2020

Integrative Single-cell RNA-Seq and ATAC-Seq Analysis of Human Foetal Liver and Bone Marrow Haematopoiesis

Regulation of haematopoiesis during human development remains poorly defined. Here, we applied single-cell (sc)RNA-Seq and scATAC-Seq analysis to over 8,000 human immunophenotypic blood cells from foetal liver and bone marrow. We inferred their differentiation trajectory and identified three highly proliferative oligopotent progenitor populations downstream from haematopoietic stem cell/multipotent progenitors (HSC/MPPs). Along this trajectory, we observed opposing patterns of chromatin accessibility and differentiation that coincided with dynamic changes in the activity of distinct lineage-specific transcription factors. Integrative analysis of chromatin accessibility and gene expression revealed extensive epigenetic but not transcriptional priming of HSC/MPPs prior to their lineage commitment. Finally, we refined and functionally validated the sorting strategy for the HSC/MPPs and achieved around 90% enrichment. Our study provides a useful framework for future investigation of human developmental haematopoiesis in the context of blood pathologies and regenerative medicine.

cell biology↗

bioRxiv2020

Predictive features of gene expression variation reveal a mechanistic link between expression variation and differential expression

For most biological processes, organisms must respond to extrinsic cues, while maintaining essential gene expression programs. Although studied extensively in single cells, it is still unclear how variation is controlled in multicellular organisms. Here, we used a machine-learning approach to identify genomic features that are predictive of genes with high versus low variation in their expression across individuals, using bulk data to remove stochastic cell-to-cell variation. Using embryonic gene expression across 75 Drosophila isogenic lines, we identify features predictive of expression variation, while controlling for expression level. Genes with low variation fall into two classes, indicating they employ different mechanisms to maintain a robust expression. In contrast, genes with high variation seem to lack both types of stabilizing mechanisms. Applying the framework to human tissues from GTEx revealed similar predictive features, indicating that promoter architecture is an ancient mechanism to control expression variation. Remarkably, expression variation features could also predict differential expression upon stress in both Drosophila and human. Differential gene expression signatures may therefore be partially explained by genetically encoded gene-specific features, unrelated to the studied treatment.

genomics↗