The functions and mechanisms of the cohesin complex in regulating the fate determinations of stem cells

1. Background & Focus

Stem cells have great applications in regenerative medicine. While transcription factors traditionally dominate fate determination research, recent 3D genomics reveals chromatin topology’s critical role. The evolutionarily conserved cohesin complex, including SMC1/3, RAD21 and STAG, organizes chromatin via loop extrusion, enabling enhancer-promoter interactions and reshaping epigenetics. It exhibits cell-type-specific functions: maintaining hematopoietic stem cell (HSC) quiescence, embryonic stem cell (ESC) pluripotency, and neural stem cell (NSC) differentiation. Dysregulation of these factors links to myelodysplastic syndromes and leukemia, highlighting its therapeutic potential.

2.1 Structure & Function

Cohesin forms a ring-shaped complex capturing DNA via SMC1/SMC3 dimers, RAD21 kleisin, and STAG regulators. NIPBL-MAU2 loads it onto chromatin, while WAPL/sororin antagonism and ESCO acetylation control its dynamics. Key functions include replication fork integrity, chromosome segregation, and 3D genome organization.

2.2 Hematopoietic Stem Cell Regulation

Cohesin complex governs HSC self-renewal, differentiation, and genomic stability via 3D genome topology. Mutations (STAG2/RAD21/SMC3) disrupt chromatin structure, which causes differentiation arrest, clonal expansion, and AML progression.

2.3 Embryonic Stem Cell Regulation

Cohesin maintains ESC pluripotency through 3D remodeling: SMC1A enables short-range loops (essential for Oct4/Nanog); STAG1/2 stabilize TADs/repress lineage genes, and RAD21 co-localizes with super-enhancers.

2.4 Other Stem Cells

NSCs: STAG1/2 balances proliferation/differentiation; loss of its function causes holoprosencephaly via ZIC2/GLI2 dysregulation.

Spermatogonial stem cells: RAD21-YAP1-NEDD4 axis sustains self-renewal; its disruption leads to azoospermia.

Intestinal/bone marrow stem cells: RAD21 stabilizes loops to inhibit differentiation/EMT; haploinsufficiency impairs DNA repair and regeneration.

2.5 Stem Cell Purities

Stem cell heterogeneity affects cohesin study results. Standardized purification is essential: HSCs (FACS-sorted Lin⁻CD34⁺CD38⁻/SLAM⁺; >95% purity), ESCs (Nestin/Sox2⁺ enrichment). This ensures accurate mechanistic insights into diseases like infertility.

2.6 Protein Interactions

We have provided an analysis of the gene regulatory network of the adhesion protein complex in stem cell proliferation and differentiation. It not only maintains chromosomal structure and cell cycle stability but also interacts with pluripotent factors, e.g., POU5F1, SOX2, NANOG, and MYC, to regulate gene expression and  influence the self-renewal and differentiation of stem cells. We have recently found that in human testicular tissues, the subunit RAD21 of the adhesion protein complex co-localizes with spermatogonial stem cell marker UCHL1, further proving its involvement in determining stem cell fate.

2.7 Dysfunction & Diseases

Cohesin complex mutations cause Cornelia de Lange/Roberts syndromes and cancers (bladder, glioblastoma, leukemia). Stem cell-specific pathologies include: HSCs: Myelodysplasia, AML; NSCs: Holoprosencephaly, neuropsychiatric disorders; Germ/intestinal stem cells: Azoospermia, pro-tumorigenesis

3. Conclusions and Perspective

Cohesin complex dynamically organizes 3D chromatin via loop extrusion and controls stem cell fate determinations by the following: spatiotemporal control of pluripotency/differentiation genes; coordinating transcription/epigenetic factors; and balancing self-renewal, metabolism, and genomic stability. Subunit mutations cause developmental disorders/cancer. Future work should explore pathological protein modifications, integrate super-resolution imaging/single-cell multi-omics, and develop tissue-specific interventions.

Sources: https://spj.science.org/doi/10.34133/research.0757