The connectionist framework for gene regulation

I show that gene regulation networks are qualitatively consistent and therefore sufficiently similar to linearly seperable connectionist networks to warrant that the connectionist framework be applied to gene regulation. On this view, natural selection designs gene regulation networks to overcome the difficulty of development. I offer some general lessons about their evolvability that can be learned by examining the generic features of connectionist networks.

Reversible acetylation of chromatin: Implication in regulation of gene expression,disease and therapeutics

The eukaryotic genome is a highly dynamic nucleoprotein complex that is comprised of DNA, histones, nonhistone proteins and RNA, and is termed as chromatin. The dynamicity of the chromatin is responsible for the regulation of all the DNA-templated phenomena in the cell. Several factors, including the nonhistone chromatin components, ATP-dependent remodeling factors and the chromatin-modifying enzymes, mediate the combinatorial post-translational modifications that control the chromatin fluidity and, thereby, the cellular functions. Among these modifications, reversible acetylation plays a central role in the highly orchestrated network. The enzymes responsible for the reversible acetylation, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), not only act on histone substrates but also on nonhistone proteins. Dysfunction of the HATs/HDACs is associated with various diseases like cancer, diabetes, asthma, cardiac hypertrophy, retroviral pathogenesis and neurodegenerative disorders. Therefore, modulation of these enzymes is being considered as an important therapeutic strategy. Although substantial progress has been made in the area of HDAC inhibitors, we have focused this review on the HATs and their small-molecule modulators in the context of disease and therapeutics. Recent discoveries from different groups have established the involvement of HAT function in various diseases. Furthermore, several new classes of HAT modulators have been identified and their biological activities have also been reported. The scaffold of these small molecules can be used for the design and synthesis of better and efficient modulators with superior therapeutic efficacy.     

染色质构象调控真核基因的表达

真核基因的表达受到各种顺式调控元件、反式作用因子、染色质DNA以及组蛋白表观遗传修饰等多因素、多层次的调控。染色质三维空间结构的变化在调控真核基因表达方面也发挥了至关重要的作用。染色质构象的变化一方面可以使增强子等调控元件与靶基因相互靠近,从而促进基因表达;同时也可能通过形成空间位阻结构阻碍调控元件作用于靶基因,抑制基因表达。虽然染色质结构变化调控真核基因表达的机制仍缺乏较为精确的分子模型,但在组蛋白修饰、核小体定位、染色体领域以及染色质间相互作用等表观遗传学研究中,已经发现有诸多证据支持染色质构象在真核基因表达调控中的重要地位。文章主要综述了染色质结构及其构象的变化等对真核基因表达调控的影响。     

Map of open and closed chromatin domains in Drosophila genome

Background

Chromatin compactness has been considered a major determinant of gene activity and has been associated with specific chromatin modifications in studies on a few individual genetic loci. At the same time, genome-wide patterns of open and closed chromatin have been understudied, and are at present largely predicted from chromatin modification and gene expression data. However the universal applicability of such predictions is not self-evident, and requires experimental verification.

Results

We developed and implemented a high-throughput analysis for general chromatin sensitivity to DNase I which provides a comprehensive epigenomic assessment in a single assay. Contiguous domains of open and closed chromatin were identified by computational analysis of the data, and correlated to other genome annotations including predicted chromatin “states”, individual chromatin modifications, nuclear lamina interactions, and gene expression. While showing that the widely trusted predictions of chromatin structure are correct in the majority of cases, we detected diverse “exceptions” from the conventional rules. We found a profound paucity of chromatin modifications in a major fraction of closed chromatin, and identified a number of loci where chromatin configuration is opposite to that expected from modification and gene expression patterns. Further, we observed that chromatin of large introns tends to be closed even when the genes are expressed, and that a significant proportion of active genes including their promoters are located in closed chromatin.

Conclusions

These findings reveal limitations of the existing predictive models, indicate novel mechanisms of epigenetic regulation, and provide important insights into genome organization and function.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-988) contains supplementary material, which is available to authorized users.     

The chromatin fingerprint of gene enhancer elements

Different cell types within a single organism are generally distinguished by strikingly different patterns of gene expression, which are dynamic throughout development and adult life. Distal enhancer elements are key drivers of spatiotemporal specificity in gene regulation. Often located tens of kilobases from their target promoters and functioning in an orientation-independent manner, the identification of bona fide enhancers has proved a formidable challenge. With the development of ChIP-seq, global cataloging of putative enhancers has become feasible. Here, we review the current understanding of the chromatin landscape at enhancers and how these chromatin features enable robust identification of tissue-specific enhancers.     

Environmental sensing by chromatin: an epigenetic contribution to evolutionary change

Chromatin structure and function are regulated by families of protein-modifying enzymes that are sensitive to a variety of metabolic and environmental agents. These enzymes, and proteins that read the modifications they maintain, constitute a system by which environmental agents, such as chemical toxins and dietary components, can directly regulate patterns of gene expression. This review describes this environmental sensing system from an evolutionary perspective. It is proposed that persistent environmentally-induced changes in gene expression patterns can cause changes in phenotype that are acted upon by natural selection, and that epigenetic processes can potentially play central roles in evolution.     

On the role of inter-nucleosomal interactions and intrinsic nucleosome dynamics in chromatin function

Evidence is emerging that many diseases result from defects in gene functions, which, in turn, depend on the local chromatin environment of a gene. However, it still remains not fully clear how chromatin activity code is ‘translated’ to the particular ‘activating’ or ‘repressing’ chromatin structural transition. Commonly, chromatin remodeling in vitro was studied using mononucleosomes as a model. However, recent data suggest that structural reorganization of a single mononucleosome is not equal to remodeling of a nucleosome particle under multinucleosomal content – such as, interaction of nucleosomes via flexible histone termini could significantly alter the mode (and the resulting products) of nucleosome structural transitions. It is becoming evident that a nucleosome array does not constitute just a ‘polymer’ of individual ‘canonical’ nucleosomes due to multiple inter-nucleosomal interactions which affect nucleosome dynamics and structure. It could be hypothesized, that inter-nucleosomal interactions could act in cooperation with nucleosome inherent dynamics to orchestrate DNA-based processes and promote formation and stabilization of highly-dynamic, accessible structure of a nucleosome array. In the proposed paper we would like to discuss the nucleosome dynamics within the chromatin fiber mainly as it pertains to the roles of the structural changes mediated by inter-nucleosomal interactions.     

Genomic studies of gene expression: regulation of the Wilson disease gene

Bacterial artificial chromosomes (BACs) have many advantages over other large-insert cloning vectors and have been used for a variety of genetic applications, including the final contigs of the human genome. We describe the utilization of a BAC construct to study gene regulation in a tissue culture-based system, using a 170-kb clone containing the entire Wilson disease (WND) locus as a model. A second BAC construct that lacked a putative negatively regulating promoter sequence was created. A nonviral method of gene delivery was applied to transfect three human cell lines stably with each construct. Our results show correct WND gene expression from the recombinant locus and quantification revealed significantly increased expression from the clone lacking the negative regulator. Comparison with conventional methods confirms the reliability of the genomic approach for thorough examination of gene expression. This experimental system illustrates the potential of BAC clones in genomic gene expression studies, new gene therapy strategies, and validation of potential molecular targets for drug discovery.     

Convergent evolution of crystallin gene regulation in squid and chicken: The AP-1/ARE connection

Previous experiments have shown that the minimal promoters required for function of the squid SL20-1 and SL11 crystallin genes in transfected rabbit lens epithelial cells contain an overlapping AP-1/antioxidant responsive element (ARE) upstream of the TATA box. This region resembles the PL-1 and PL-2 elements of the chicken B 1-cry stallin promoter which are essential for promoter function in transfected primary chicken lens epithelial cells. Here we demonstrate by site-directed mutagenesis that the AP-1/ARE sequence is essential for activity of the squid SL20-1 and SL11 promoters in transfected embryonic chicken lens cells and fibroblasts. Promoter activity was higher in transfected lens cells than in fibroblasts. Electrophoretic mobility shift and DNase protection experiments demonstrated the formation of numerous complexes between nuclear proteins of the embryonic chicken lens and the AP-1/ARE sequences of the squid SL20-1 and SL11 crystallin promoters. One of these complexes comigrated and cross-competed with that formed with the PL-1 element of the chicken B1-crystallin promoter. This complex formed with nuclear extracts from the lens, heart, brain, and skeletal muscle of embryonic chickens and was eliminated by competition with a consensus AP-1 sequence. The nonfunctional mutant AP-1/ ARE sequences did not compete for complex formation. These data raise the intriguing possibility that entirely different, nonhomologous crystallin genes of the chicken and squid have convergently evolved a similar cis-acting regulatory element (AP-1/ARE) for high expression in the lens. Correspondence to: S. I. Tomarev