scholarly journals bHLH-PAS proteins: Functional specification through modular domain architecture

2013 ◽  
Vol 1 (2) ◽  
Author(s):  
AK Michael ◽  
CL Partch
Author(s):  
Christopher H. Douse ◽  
Iva A. Tchasovnikarova ◽  
Richard T. Timms ◽  
Anna V. Protasio ◽  
Marta Seczynska ◽  
...  

SummaryThe Human Silencing Hub (HUSH) complex epigenetically represses retroviruses, transposons and genes in vertebrates. HUSH therefore maintains genome integrity and is central in the interplay between intrinsic immunity, transposable elements and transcriptional regulation. Comprising three subunits – TASOR, MPP8 and Periphilin – HUSH regulates SETDB1-dependent deposition of the transcriptionally repressive epigenetic mark H3K9me3 and recruits MORC2 to modify local chromatin structure. However the mechanistic roles of each HUSH subunit remain undetermined. Here we show that TASOR lies at the heart of HUSH, providing a platform for assembling the other subunits. Targeted epigenomic profiling supports the model that TASOR binds and regulates H3K9me3 specifically over LINE-1 repeats and other repetitive exons in transcribed genes. We find TASOR associates with several components of the nuclear RNA processing machinery and its modular domain architecture bears striking similarities to that of Chp1, the central component of the yeast RNA-induced transcriptional silencing (RITS) complex. Together these observations suggest that an RNA intermediate may be important for HUSH activity. We identify the TASOR domains necessary for HUSH assembly and transgene repression. Structural and genomic analyses reveal that TASOR contains a poly-ADP ribose polymerase (PARP) domain dispensable for assembly and chromatin localization, but critical for epigenetic regulation of target elements. This domain contains a degenerated and obstructed active site and has hence lost catalytic activity. Together our data demonstrate that TASOR is a pseudo-PARP critical for HUSH complex assembly and H3K9me3 deposition over its genomic targets.


2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Nadia A. Atai ◽  
Scott D. Ryan ◽  
Rashmi Kothary ◽  
Xandra O. Breakefield ◽  
Flávia C. Nery

Most cases of early onset DYT1 dystonia in humans are caused by a GAG deletion in theTOR1Agene leading to loss of a glutamic acid (ΔE) in the torsinA protein, which underlies a movement disorder associated with neuronal dysfunction without apparent neurodegeneration. Mutation/deletion of the gene (Dst) encoding dystonin in mice results in a dystonic movement disorder termeddystonia musculorum, which resembles aspects of dystonia in humans. While torsinA and dystonin proteins do not share modular domain architecture, they participate in a similar function by modulating a structural link between the nuclear envelope and the cytoskeleton in neuronal cells. We suggest that through a shared interaction with the nuclear envelope protein nesprin-3α, torsinA and the neuronal dystonin-a2 isoform comprise a bridge complex between the outer nuclear membrane and the cytoskeleton, which is critical for some aspects of neuronal development and function. Elucidation of the overlapping roles of torsinA and dystonin-a2 in nuclear/endoplasmic reticulum dynamics should provide insights into the cellular mechanisms underlying the dystonic phenotype.


2020 ◽  
Author(s):  
Deon T. Benton ◽  
David H. Rakison

The ability to reason about causal events in the world is fundamental to cognition. Despite the importance of this ability, little is known about how adults represent causal events, what structure or form those representations take, and what the mechanism is that underpins such representations. We report four experiments with adults that examine the perceptual basis on which adults represent four-object launching sequences (Experiments 1 and 2), whether adults representations reflect sensitivity to the causal, perceptual, or causal and perceptual relation among the objects that comprise such sequences (Experiment 3), and whether such representations extend beyond spatiotemporal contiguity to include other low-level stimulus features such as an object’s shape and color (Experiment 4). Based on these results of the four experiments, we argue that a domain-general associative mechanism, rather a modular, domain-specific, mechanism subserves adults’ representations of four-object launching sequences.


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