Sin3a, also known as switch-independent 3a, is a multifunctional transcription regulator. It is a central scaffold protein of the SIN3/histone deacetylase (HDAC) transcriptional repressor complex, playing a role in regulating epigenetic changes, such as DNA and histone methylation [1,2,3]. Sin3a is involved in numerous biological processes, including cell development, differentiation, and somatic cell reprogramming, and is associated with various diseases like pulmonary arterial hypertension (PAH) and breast cancer [1,4]. Genetic models, especially knockout (KO) mouse models, are valuable for studying Sin3a's functions.

In a PAH study, Sin3a dysregulation was detected in patients and rodent models, which was strongly associated with decreased BMPR2 expression. Overexpression of Sin3a inhibited human pulmonary arterial smooth muscle cells proliferation and upregulated BMPR2 expression by preventing promoter methylation, suggesting its protective role in PAH [1].

In somatic cell reprogramming, knockdown of Sin3a significantly impaired mesenchymal-to-epithelial transition (MET) at the early stage of reprogramming and iPSC generation, revealing its role as an epigenetic coactivator cooperating with Tet1 [2].

In breast cancer, miR-183-mediated suppression of Sin3A promoted breast cancer cell migration, invasion, and metastasis, with patients having high miR-183 and low Sin3A levels having the shortest overall survival [4].

In mouse early embryos, specific depletion of Sin3a arrested embryos at the morula stage, affecting cell proliferation, the first cell fate decision, and genome-wide DNA methylation, and this could be rescued by Hdac1 expression [5].

In porcine early embryos, SIN3A depletion caused a developmental arrest at the two-cell stage, likely involving the regulation of CCNB1 expression [6].

Conditional deletion of Sin3a within Foxp3+ Tregs in mice led to fatal autoimmunity, reduced Treg numbers, and impaired Treg function due to decreased Foxp3 transcription and protein stability [7].

In primary CD4 T cells, Sin3A inactivation in vivo hindered thymocyte development and peripheral T-cell survival, and in vitro, Sin3A-deficient cells failed to properly upregulate Th17-related genes but enriched IL-2+ and FOXP3+ cells [8].

In embryonic stem cells, Tet2 deficiency diminished Sin3a at active enhancers and promoters [9].

In conclusion, Sin3a is crucial in various biological processes, including cell development, reprogramming, and immune cell regulation. Through model-based research, especially KO/CKO mouse models, we have gained insights into its role in diseases such as PAH and breast cancer. These findings highlight Sin3a's importance in understanding disease mechanisms and potentially developing new therapeutic strategies.