In a comprehensive recent study, the molecular basis of the powerful gene regulatory activity of the cohesin complex was revealed. This finding illustrates its crucial involvement in cellular processes and connects it to rare genetic disorders. This study emphasizes the organization of cohesin and its isoforms within human cells. It further discusses the mechanisms by which mutations in cohesin-related genes underlie developmental malformations.
Cohesin is an essential protein complex that forms a doughnut-shaped structure. This unique structure intricately coils and folds around DNA, affecting its shape and organization. This complex is composed of four subunits: SMC1, SMC3, and SCC1/RAD21, forming the backbone of the cohesin mechanism. The existence of two isoforms in human cells—STAG-1 cohesin and STAG-2 cohesin—makes things even more complicated. While such isoforms are likely to differ in their composition of subunits, this isomerism could yield diversifying functional roles on gene regulation.
The Role of Cohesin in Gene Regulation
The connection between the cohesin complex and gene regulation goes beyond its role on topologically associated domains, as cohesin forms dynamic interactions with numerous transcription factors, regulating gene expression. Recently, researchers have learned that the NIPBL/MAU2 complex is essential for correctly placing cohesin at enhancers. These enhancers are the strategic sites where the activation of any gene begins. Localization is extremely important for ternary complex formation. In this intricate ensemble, transcription factors like the glucocorticoid receptor (GR) are seen making contact with NIPBL and MAU2.
“This NIPBL-MAU2-GR ternary complex modulates the transcription since it facilitates the interaction of the glucocorticoid receptor (GR) with NIPBL and MAU2, which is the cohesin-loading factor. When the GR interacts with these two proteins, it alters the structure of chromatin and affects the process of gene expression,” – Alba Jiménez-Panizo and Andrea Alegre-Martí.
For the first time, this unexpected finding emphasized that cohesin’s key role is to preserve DNA’s architecture. Additionally, it reveals the role-cohesin in regulating the transcriptional landscape of cells. This machinery is critical to make sure that millions of genes in the human body are expressed at the right time and exact location. Its role is very important in development.
Cohesin Isoforms and Their Functional Differences
This distinction between STAG-1 and STAG-2 cohesin isoforms begs the question of what their distinct roles are in cellular function. Each isoform carries distinct regulatory properties, which might add up to the complex manner in which genes are regulated in response to signals from multiple environmental cues. By understanding these disparities we can learn how dysregulation can drive disease.
Recent studies have identified at least 25 distinct proteins that modulate the activity of cohesin subunits and/or affect their biological function. These regulatory proteins add to the intricate detail of cohesin’s dualistic involvement in gene expression.
“To date, researchers have described 25 proteins that regulate these subunits and their biological function,” – Professor Estébanez-Perpiñá.
Digging into these legislative levers is of utmost importance. It will advance our knowledge of how different disruptions in cohesin function can cause these disorders.
Implications for Cohesinopathies
Cohesinopathies are rare genetic disorders associated with mutations in genes that encode the cohesin complex. These are perhaps best exemplified by the syndromes of Cornelia de Lange (CdLS) and Roberts. These chromosomal microdeletions and microduplications frequently cause polygenic developmental malformations of multiple organs which are caused by the dysregulation of such vast genomic reorganization.
In particular, Cornelia de Lange syndrome is well known to be caused by mutations in major genes of interest NIPBL, SMC1A, HDAC8, RAD21 and SMC3. Mutations in these genes are numerous and complicated and warrant further discussion. Importantly, they have a major impact on cohesin itself, as well as the proteins that control its function.
“These mutations affect key subunits of both cohesin and the proteins that regulate its organization and function. Understanding the molecular mechanisms by which the complexes do not form correctly and cause the chromosomes not to be organized in a functional way is key to understanding the disease,” – The researchers.
As research progresses, understanding these molecular mechanisms may lead to better diagnostic tools and therapeutic strategies for individuals affected by cohesinopathies.