A pinboard by
Zeenat Shigan

Grad student, University of Kashmir


Eukaryotic genome is maintained as a highly complex nucleoprotein structure called chromatin, which supports and controls all functions of the genome. The organization of eukaryotic genome into chromatin controls accessibility to the factors required for gene transcription, DNA replication, recombination and repair. Chromatin exists in two flavors inside the cell, euchromatin and heterochromatin, distinguished on the basis of their appearance, structure, localization and function. While most of the actively transcribed genes are found in the euchromatin, heterochromatin is thought to be transcriptionally inert. In fission yeast, domains of heterochromatin are found at pericentromeric DNA regions, mating type locus and telomeres. Assembly of heterochromatin in fission yeast requires the methylation of histone H3 at lysine 9 (H3K9) mediated by the sole H3K9 methyltransferase, Clr4. H3K9me creates binding sites for the chromodomain containing proteins Swi6, Chp1, Chp2, and Clr4. H3K9 methylation requires components of the RNA interference (RNAi) machinery. RNAi is a conserved silencing pathway that is triggered by double-stranded RNA (dsRNA), which is processed into small interfering RNA (siRNA) of ~22 nucleotides in size by the Dicer ribonuclease. RNAi in fission yeast is triggered by double-stranded RNA (dsRNA) derived from noncoding centromere outer repeat transcripts produced during S phase by RNA polymerase II. Dicer (Dcr1) cleaves these dsRNA molecules into short interfering RNAs (siRNAs) that guide the Argonaute (Ago1)-containing RITS effector complex to homologous nascent transcripts by sequence complementarity. Association of the RITS complex (Ago1, Tas3, and Chp1) with chromatin is facilitated by binding of the chromodomain protein Swi6 and Chp1 to H3K9me nucleosomes, which drives a self-enforcing loop coupling spreading of H3K9me with RITS binding. Formation of heterochromatin is required for centromere formation, heritable gene silencing, repression of recombination, sister chromatid cohesion, and maintenance of telomere stability. Swi6 protein is central to the assembly and spread of heterochromatin containing histone H3K9 methylation. It is thought to reduce RNA polymerase occupancy both by recruiting accessory silencing factors and by forming less-accessible chromatin structures. Mechanistically how Swi6 mediates silencing is not fully understood. Other accessary proteins that work in coordination with Swi6 have not been completely elucidated.


Modulating Epigenetic HAT activity for reinstating acetylation homeostasis: A promising therapeutic strategy for Neurological disorders

Abstract: Epigenetic mechanisms are emerging as a fundamental regulatory switch in neuronal function. Acetylation homeostasis governed by the antagonistic activities of HATs and HDACs play a critical role in neuronal gene activity. It is now becoming increasingly clear that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are caused by aberrant changes in chromatin acetylation. Several HATs have been shown to be vital for neuronal processes such as synaptic plasticity and memory formation. Thus not surprisingly, dysregulation of such HATs has been implicated in the pathogenesis of several neurodegenerative diseases including Huntington’s disease (HD) and Alzheimer’s disease (AD). The current therapeutic strategy involves the use of small-molecule histone deacetylase inhibitors to compensate the acetylation deficits arising due to loss of HAT activity. Despite the promising therapeutic effects, the lack of isoform (target) specificity of HDACi raises concerns regarding their applicability. Mounting evidences about the role of HATs in neuronal survival, learning and memory has triggered a new wave of modulating specific HATs as a novel therapeutic option to tackle neurodegenerative diseases. In this review we focus on different HAT families and the critical roles they play in neural development and how the altered acetylation homeostasis culminates in neurodegeneration. Further, we describe the HDACi based therapeutic approach and its flip side in overcoming neurodegenerative diseases. Furthermore, we discuss the therapeutic potential of HAT modulators in reinstating acetylation homeostasis to ameliorate neurodegenerative disorders.

Pub.: 10 Jul '16, Pinned: 28 Jun '17