Independence of 3D chromatin conformation and gene regulation during Drosophila dorsoventral patterning

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The relationship between the 3D organisation of chromatin inside the nucleus and the regulation of gene expression remains unclear. While disruption of domains and domain boundaries can lead to mis-expression of developmental genes, acute depletion of key regulators of genome organisation, such as CTCF and cohesin, and major reorganisation of genomic regions have relatively small effects on gene expression. Therefore, it is unclear whether changes in gene expression and chromatin state drive chromatin reorganisation, or whether changes in chromatin organisation facilitate cell type-specific activation of genes and their regulatory elements. Here, using the <jats:italic>Drosophila melanogaster</jats:italic> dorsoventral patterning system as a model, we demonstrate the independence of 3D chromatin organisation and developmental gene regulation. We define tissue-specific enhancers and link them to expression patterns at the single-cell level using single cell RNA-seq. Surprisingly, despite tissue-specific differences in chromatin state and gene expression, 3D chromatin organisation is maintained across tissues. Our results provide strong evidence that tissue-specific chromatin conformation is not required for tissue-specific gene expression, but rather acts as an architectural framework to facilitate proper gene regulation during development.</jats:p>

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

“…Notably, stable TAD structures observed in these primary tissues contrast previous reports of chromatin organization in cell lines derived from prostate cells 44,62 , highlighting the necessity of low-input protocols and primary tissues 40 . Our findings further support recent reports of shared higher-order chromatin organization among phenotypically distinct cell types in model organisms 2,28,32,[63][64][65] . Taken together, this body of evidence suggests that large disruptions to TADs and compartments may constrain the transformation of normal to cancer cells or the divergent subtyping within prostate tumours.…”

Enhancers in disease: molecular basis and emerging treatment strategies

“…On the one hand, cohesin-mediated enhancer-promoter loops across cell lines correlate with gene expression [96] and mutations to the cohesin complex result in loss of gene expression [97]. On the other hand, multiple studies have shown that changes in TAD organization do not translate to changes in gene expression [98,99].…”

The role of insulators and transcription in 3D chromatin organisation of flies

“…Furthermore, even in the case when a promoter has a 3D contact with a regulatory sequence, less than 10% of genes display differential expression when the contact is lost, but the same is true at maintained loops. This suggests that the presence of chromatin loops would not be essential for controlling gene transcription in the majority of cases 58,[63][64][65] .…”