Biology subjects

Zehnder, T.

Publications and source records attributed to Zehnder, T..

3 recordsLinked to original sources

bioRxiv2021

Promoter repression and 3D-restructuring resolves divergent developmental gene expression in TADs

Cohesin loop extrusion facilitates precise gene expression by continuously driving promoters to sample all enhancers located within the same topologically-associated domain (TAD). However, many TADs contain multiple genes with divergent expression patterns, thereby indicating additional forces further refine how enhancer activities are utilised. Here, we unravel the mechanisms enabling a new gene, Rex1, to emerge with divergent expression within the ancient Fat1 TAD in placental mammals. We show that such divergent expression is not determined by a strict enhancer-promoter compatibility code, intra-TAD position or nuclear envelope-attachment. Instead, TAD-restructuring in embryonic stem cells (ESCs) separates Rex1 and Fat1 with distinct proximal enhancers that independently drive their expression. By contrast, in later embryonic tissues, DNA methylation renders the inactive Rex1 promoter profoundly unresponsive to Fat1 enhancers within the intact TAD. Combined, these features adapted an ancient regulatory landscape during evolution to support two entirely independent Rex1 and Fat1 expression programs. Thus, rather than operating only as rigid blocks of co-regulated genes, TAD-regulatory landscapes can orchestrate complex divergent expression patterns in evolution. HIGHLIGHTSO_LINew genes can emerge in evolution without taking on the expression pattern of their surrounding pre-existing TAD. C_LIO_LICompartmentalisation can restructure seemingly evolutionarily stable TADs to control a promoters access to enhancers. C_LIO_LILamina-associated domains neither prevent transcriptional activation nor enhancer-promoter communication. C_LIO_LIRepression rather than promoter-specificity refines when genes respond to promiscuous enhancer activities in specific tissues. C_LI

genetics↗

bioRxiv2021

Integrative annotation of genomic features reveal functional elements and epigenetic landscapes in the developing zebrafish

Zebrafish, a popular model for embryonic development and for modelling human diseases, has so far lacked a systematic functional annotation programme akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created the first central repository to store and process zebrafish developmental functional genomic data. Our Data Coordination Center (https://danio-code.zfin.org) combines a total of 1,802 sets of unpublished and reanalysed published genomics data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements in development, including novel classes with distinct features dependent on their activity in time and space. We delineated the distinction between regulatory elements active during zygotic genome activation and those active during organogenesis, identifying new aspects of how they relate to each other. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predict functional relationships between them beyond sequence similarity, extending the utility of zebrafish developmental genomics to mammals.

developmental biology↗

bioRxiv2021

Astrocytic VMAT2 in the developing prefrontal cortex is required for normal grooming behavior in mice

Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD).

neuroscience↗