Chemical Decorations of “MARs” Residents in Orchestrating Eukaryotic Gene Regulation

Abstract

Genome organization plays a crucial role in gene regulation, orchestrating multiple cellular functions. A meshwork of proteins constituting a three-dimensional (3D) matrix helps in maintaining the genomic architecture. Sequences of DNA that are involved in tethering the chromatin to the matrix are called scaffold/matrix attachment regions (S/MARs), and the proteins that bind to these sequences and mediate tethering are termed S/MAR-binding proteins (S/MARBPs). The regulation of S/MARBPs is important for cellular functions and is altered under different conditions. Limited information is available presently to understand the structure–function relationship conclusively. Although all S/MARBPs bind to DNA, their context- and tissue-specific regulatory roles cannot be justified solely based on the available information on their structures. Conformational changes in a protein lead to changes in protein–protein interactions (PPIs) that essentially would regulate functional outcomes. A well-studied form of protein regulation is post-translational modification (PTM). It involves disulfide bond formation, cleavage of precursor proteins, and addition or removal of low-molecular-weight groups, leading to modifications like phosphorylation, methylation, SUMOylation, acetylation, PARylation, and ubiquitination. These chemical modifications lead to varied functional outcomes by mechanisms like modifying DNA–protein interactions and PPIs, altering protein function, stability, and crosstalk with other PTMs regulating subcellular localizations. S/MARBPs are reported to be regulated by PTMs, thereby contributing to gene regulation. In this review, we discuss the current understanding, scope, disease implications, and future perspectives of the diverse PTMs regulating functions of S/MARBPs.

Gene Augmentation of CHM Using Non-Viral Episomal Vectors in Models of Choroideremia

“…Considering the drawbacks associated with viral gene therapy, non-viral alternatives are of great interest for IRDs, with one potential strategy being the use of plasmid vectors with extensive cloning capacity that incorporate a DNA motif known as the scaffold/matrix attachment region (S/MAR). S/MARs are genomic sequences at which the chromatin anchors to the nuclear matrix proteins during interphase, a function thought to be involved in gene regulation [22,23]. When incorporated into plasmids, they promote episomal maintenance (preventing genome integration), mitotic stability, and protection against epigenetic silencing, producing persistent gene expression both in vitro and in vivo [24,25].…”

Involvement of Thyroid Hormones in Brain Development and Cancer

“…It has also been clearly established that brain development and maturation, as well as adult neuronal plasticity, strictly depend on dynamic changes in gene expression, and that such modifications in transcriptional programs are in turn determined by chromatin organization [ 20 , 21 , 22 , 23 ]. In order to modulate chromatin structure, thus regulating the accessibility of genes to RNA polymerase, a few interrelated mechanisms are required: (i) post-translational modification of histone proteins; (ii) modification of site-specific DNA methylation; (iii) changes in the activity of ATP-dependent chromatin remodeling complexes, such as the chromodomain helicase DNA-binding (Chd) family of enzymes; and (iv) synthesis and incorporation into chromatin of histone variants [ 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Now, the nuclear receptors for thyroid hormones (THRs) can bind to chromatin and, depending on the presence of T3 and/or other regulatory factors, can recruit chromatin remodeling complexes and/or histone-modifying activities, thus causing the chromatin structure and gene expression to change [ 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”