The Functions and Mechanisms of the Cohesin Complex in Regulating the Fate Determinations of Stem Cells
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The Functions and Mechanisms of the Cohesin Complex in Regulating the Fate Determinations of Stem Cells

10/10/2025 Science and Technology Review Publishing House
Conventional studies on stem cell fates are primarily focused on transcription factors, with the limited consideration for 3D genome architecture. The cohesin complex dynamically restructures chromatin topology to precisely coordinate enhancer-promoter interactions, which offers novel insights into fate decisions of hematopoietic stem cells, embryonic stem cells, and neural stem cells. This mechanisms provide significant applications for regenerative medicine and cancer therapy. Prof. Zuping He’s team at Hainan Medical University has reviewed multidimensional regulatory networks of the complex in ‘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.
The Functions and Mechanisms of the Cohesin Complex in Regulating the Fate Determinations of Stem Cells

The complete study is accessible via DOI:10.34133/research.0757
https://spj.science.org/doi/10.34133/research.0757
Title: The Functions and Mechanisms of the Cohesin Complex in Regulating the Fate Determinations of Stem Cells
Authors: JIANGHONG XIANG, YIHAN LAI, AND ZUPING HE
Journal: RESEARCH，10 Jul 2025，Vol 8， Article ID: 0757
DOI:10.34133/research.0757
Archivos adjuntos
  • Fig. 1. Structures of the cohesin complex. (A) Core structures of the cohesin complex. The complex cohesin is composed of 4 core subunits, namely, SMC1, SMC3, RAD21, and STAG, and there are mitosis-specific and meiosis-specific cohesin complexes. (B) WAPL negatively regulates sister chromatid cohesion by promoting cohesin dissociation from chromatin, whereas sororin stabilizes cohesin–chromatin binding by antagonizing WAPL function. The dynamic antagonism between these 2 modulators accurately regulates the loading/unloading balance of cohesin. (C) The cohesin complex synergizes with CTCF proteins to form chromatin ring structures that define topologically associating domain (TAD) boundaries to regulate 3-dimensional (3D) genome spatial organization.
  • Fig. 2. Dynamic regulation of the cohesin complex in the cell cycle of stem cells. (A) The cohesin complex is involved in regulating the G1, S (DNA synthesis), G2, and M (mitosis) phases of stem cell cycles by the genes ESCO1/ESCO2, Sororin, CDK1/PLK1, and Separase. (B) The cohesin complex supports the 3D structure of the genome by mediating the extrusion of chromatin loops, adhering sister chromatids to ensure accurate segregation after DNA replication, and maintaining their physical linkage to support homologous recombination repair during DNA damage repair.
  • Fig. 3. Functions and mechanisms of the cohesin complex regulation in HSCs and the development of AML. (A) Normal cohesin complex in controlling loop extrusion, DNA replication, and DNA repair of HSCs. The cohesin complex is involved in the construction of 3D genomic structures (e.g., TADs) and the regulation of gene expression by dynamically forming and promoting the extension of chromatin loops through loop extrusion. The cohesin complex also ensures DNA replication accuracy by stabilizing replication forks and promotes homologous recombination through the maintenance of sister chromatid cohesion in DNA damage repair, thereby safeguarding genome integrity in HSCs. (B) Mutant cohesin complex in mediating HSC fate decisions and diseases. The mutant cohesin complex affects the expression and chromatin accessibility of HSC self-renewal and differentiation genes, which leads to an enhancement of HSC self-renewal. The mutations of the cohesin complex result in AML.
  • Fig. 4. Functions and mechanisms of cohesin complex regulation in ESCs. (A) The cohesin complex dynamically regulates genome topology and chromatin loops. (B and C) The cohesin complex affects the genomic stability (B) and transcriptional regulation (C) of ESCs by regulating the genomic topology, E-P interaction, and epigenetic state. 2C-LCs, 2-cell-like cells.
  • Fig. 5. Gene networks, functional enrichment, and protein interaction of the cohesin complex in stem cells. (A and B) The gene interaction network of the 4 subunits of cohesin complex (SMC1, SMC3, RAD21, and STAG), which contains the genes CTCF, CSM5, and SMC6 involved in sister chromatid cohesion, segregation, and DNA repair and the key nodes CTCF and SMC3 to maintain the stability of the network. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that cohesin-related genes are significantly enriched in the cell cycle, chromosome segregation (e.g., sister chromatid cohesion), and other processes and pathways, highlighting their important roles in the maintenance of the cell cycle and chromosome structure. (C) Interaction network of the subunits of the cohesin complex and pluripotency factors (e.g., POU5F1, NANOG, and SOX2) and stem cell proliferation (MYC). (D) RAD21 is colocalized with UCHL1 in human testicular tissues. BP, Biological Process; CC, Cellular Component; MF, Molecular Function; DAPI, 4′,6-diamidino-2-phenylindole.
10/10/2025 Science and Technology Review Publishing House
Regions: Asia, China
Keywords: Health, Medical, Science, Life Sciences

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