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BMC genomics2026; doi: 10.1186/s12864-026-12840-6

ATAC-seq and RNA-seq reveal key genes and pathways regulating lactation in the mammary gland of Yili horses.

Abstract: BACKGROUND: Mammary gland development and lactation are dynamic biological processes governed by coordinated changes in chromatin accessibility and gene expression. RESULTS: We performed paired ATAC-seq and RNA-seq profiling to characterize stage-associated chromatin accessibility and transcriptional programs in the Yili horse mammary gland. Using a conservative overlap-based integration, we prioritized candidate genes showing concordant changes across both layers as hypothesis-generating signals for future functional studies. We sequenced mammary gland tissues from early lactation (S1) and peak lactation (S2) stages. We identified 32,187 S1-specific peaks and 46,661 S2-specific peaks. Upregulated genes were enriched in biological processes related to cell differentiation, tissue development, and signaling pathways, including PI3K-Akt, JAK-STAT, and Rap1 signaling, which may be involved in lactation regulation. In addition, motif enrichment analysis suggested several key transcription factors, including STAT5, SMAD4, and KLF3. Integration of ATAC-seq and RNA-seq data highlighted 22 differentially expressed genes (DEGs) with altered chromatin accessibility, including PTGES, NFATC4, RET, RGS2, and EQMHCB2, which are involved in the oxytocin signaling pathway, glutathione metabolism, and Wnt signaling. CONCLUSIONS: This study presents a stage-resolved atlas of chromatin accessibility and gene expression in the Yili horse mammary gland, suggesting candidate pathways and genes for further validation.
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Publication Date: 2026-04-22 PubMed ID: 42015003DOI: 10.1186/s12864-026-12840-6Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study used two genome-wide methods to map open DNA regions and active genes in Yili horse mammary glands at early and peak lactation, revealing more open chromatin at peak lactation and pinpointing pathways and transcription factors likely controlling milk production. The integrated analysis nominated 22 genes with coordinated chromatin and expression changes—implicating oxytocin, Wnt, and antioxidant pathways—as high-priority candidates for future functional tests.

What the researchers asked and why it matters

  • Question: Which genes, regulatory DNA elements, and pathways control the transition from early to peak lactation in the horse mammary gland?
  • Rationale: Lactation depends on stage-specific gene regulation; understanding these programs can clarify fundamental mammary biology and guide improvement of equine lactation health and productivity.
  • Gap addressed: Equine mammary regulation is less characterized than human/mouse/bovine; a stage-resolved regulatory atlas for horses has been lacking.

How the study was done (methods at a glance)

  • Samples: Mammary gland tissues were collected at two physiological stages—early lactation (S1) and peak lactation (S2)—from Yili horses.
  • ATAC-seq: Assessed chromatin accessibility to identify regulatory DNA regions (“peaks”) that are open/active at each stage.
  • RNA-seq: Quantified gene expression and identified differentially expressed genes (DEGs) between S1 and S2.
  • Integration strategy: Used a conservative overlap-based approach that links stage-specific open chromatin regions to nearby genes with concordant expression changes, enriching for high-confidence regulatory targets.
  • Downstream analyses: Performed pathway enrichment (e.g., PI3K-Akt, JAK-STAT, Rap1), transcription factor motif enrichment, and functional annotation of candidate genes.

Key results

  • More open chromatin at peak lactation: Identified 32,187 S1-specific peaks versus 46,661 S2-specific peaks, indicating broader regulatory activation during peak milk production.
  • Upregulated processes: Genes with higher expression at S2 were enriched for cell differentiation, tissue development, and signaling pathways central to lactation physiology.
  • Highlighted signaling pathways: PI3K-Akt, JAK-STAT, and Rap1 signaling emerged as prominent, aligning with known roles in cell survival, prolactin/STAT5-mediated milk synthesis, and adhesion/cytoskeletal dynamics.
  • Transcription factor motifs: Enrichment for STAT5, SMAD4, and KLF3 motifs implicates these regulators in stage-specific control of mammary programs.
  • Integrated candidates: 22 DEGs showed coordinated changes in chromatin accessibility and expression, including PTGES, NFATC4, RET, RGS2, and EQMHCB2, intersecting oxytocin signaling, glutathione metabolism, and Wnt signaling.
  • Outcome: A stage-resolved atlas of regulatory DNA and transcription in the Yili horse mammary gland, providing a prioritized list of genes and pathways for functional follow-up.

Biological interpretation and significance

  • Peak lactation regulatory expansion: The larger number of S2-specific accessible regions suggests increased engagement of enhancers/promoters to sustain high secretory activity and structural remodeling at peak output.
  • STAT5 axis: Enrichment of STAT5 motifs aligns with prolactin-driven activation of milk protein and lipid synthesis genes; this corroborates conserved lactation control observed in other mammals.
  • TGF-beta/SMAD4 balance: SMAD4 (a central TGF-β mediator) motif enrichment hints at context-dependent restraint or remodeling signals that fine-tune proliferation, differentiation, and extracellular matrix dynamics during lactation.
  • KLF family roles: KLF3 motif enrichment suggests contributions to epithelial differentiation and metabolic gene programs required for sustained milk production.
  • Pathway convergence: PI3K-Akt (cell survival/metabolism), JAK-STAT (lactogenic transcription), and Rap1 (cell adhesion/polarity) converge to maintain secretory epithelial function and alveolar integrity under high demand.
  • Stress and contraction components: Glutathione metabolism points to antioxidant defenses during intense biosynthesis; oxytocin signaling underpins myoepithelial contraction for milk ejection, integrating neural-hormonal control with gene regulation.

What ATAC-seq and RNA-seq each added

  • ATAC-seq: Mapped stage-specific open chromatin, revealing thousands of candidate regulatory elements whose accessibility shifts between S1 and S2.
  • RNA-seq: Identified genes whose expression changes between stages, flagging functional pathways active at peak lactation.
  • Combined value: Overlap of accessible elements with DEGs increases confidence that identified genes are under active regulatory control, enhancing biological interpretability over either assay alone.

Details on the integrated candidate genes

  • PTGES (prostaglandin E synthase): Links eicosanoid signaling to mammary function, potentially modulating local inflammation, vascular tone, and alveolar activity during lactation.
  • NFATC4: A calcium-responsive transcription factor; oxytocin-induced calcium fluxes could interface with NFAT signaling to coordinate contraction-related gene networks.
  • RET: A receptor tyrosine kinase implicated in developmental morphogenesis; may contribute to ductal/alveolar maintenance or epithelial-stromal communication during peak function.
  • RGS2: Modulates G protein-coupled receptor signaling; could tune oxytocin and other GPCR pathways governing milk ejection and secretory dynamics.
  • EQMHCB2: An equine immune-related gene (likely MHC-associated); upregulation and accessibility shifts may reflect immune surveillance and tissue homeostasis in the lactating gland.
  • Collective pathways: The set spans oxytocin signaling, antioxidant defense (glutathione), and Wnt developmental signaling—together supporting contraction, protection from oxidative stress, and epithelial state control.

Strengths of the study

  • Stage-resolved profiling: Direct comparison of early versus peak lactation captures dynamic regulatory transitions essential to milk production.
  • Multi-omic design: Paired ATAC-seq and RNA-seq increases mechanistic insight by linking regulatory DNA to transcriptional outputs.
  • Conservative integration: Prioritizes high-confidence gene–regulatory element matches, reducing false positives for downstream validation.
  • Biological coherence: Enrichment of canonical lactation regulators (STAT5, JAK-STAT) supports validity and cross-species relevance.

Limitations and cautions

  • Sample details: The abstract does not report the number of animals or replicates; limited replication would constrain statistical power and generalizability.
  • Tissue heterogeneity: Bulk assays average signals across epithelial, myoepithelial, stromal, immune, and endothelial cells, potentially obscuring cell-type-specific regulation.
  • Peak-to-gene linkage: Proximity-based overlap misses distal enhancer–promoter interactions that are not linearly adjacent; some causal regulatory elements may be overlooked.
  • Correlative evidence: Accessibility and expression changes imply regulation but do not establish causality; functional perturbations are needed.
  • Two-stage snapshot: Intermediate time points (late pregnancy, involution) are not profiled, limiting trajectory inference.

Suggested follow-up experiments

  • Functional perturbations: CRISPRi/a or siRNA/overexpression for STAT5, SMAD4, KLF3, PTGES, NFATC4, RET, and RGS2 in primary equine mammary epithelial cells to test causal roles in lactation gene programs.
  • ChIP-seq/CUT&RUN: Map STAT5, SMAD4, and KLF3 binding at S1 and S2 to validate direct target genes and confirm motif-based predictions.
  • Single-cell multi-omics: scRNA-seq and scATAC-seq to resolve cell-type-specific regulatory changes and uncover rare subpopulations active at peak lactation.
  • Chromatin conformation: Hi-C/HiChIP/PLAC-seq to connect distal enhancers to target promoters beyond proximity-based overlap.
  • Physiological coupling: Integrate hormone levels (prolactin, oxytocin), milk yield/composition, and tissue histology with molecular data to link regulation to function.
  • Comparative analyses: Cross-species meta-analysis (horse, cow, mouse, human) to define conserved cores versus equine-specific regulatory modules.

Potential applications

  • Equine health: Biomarkers for lactation adequacy, early detection of lactation failure, and monitoring of oxidative stress in the gland.
  • Breeding and management: Candidate genes and pathways for selection or nutritional/husbandry interventions to support peak lactation performance.
  • Veterinary therapeutics: Targeted modulation of oxytocin/STAT5/PI3K-Akt pathways to aid milk let-down or recovery from lactational stress, pending safety validation.

How to interpret the peak numbers

  • S1-specific peaks (32,187): Regions preferentially open in early lactation, potentially linked to initiation and early remodeling programs.
  • S2-specific peaks (46,661): Regions preferentially open at peak lactation, consistent with heightened transcriptional and secretory demands.
  • Biological implication: The net increase at S2 suggests expansion of active regulatory networks as lactation intensifies.

Take-home messages

  • Peak lactation in Yili horses features expanded chromatin accessibility and activation of core lactation pathways (JAK-STAT/STAT5, PI3K-Akt, Rap1).
  • Motif and integration analyses nominate STAT5, SMAD4, KLF3, and 22 high-confidence genes (including PTGES, NFATC4, RET, RGS2, EQMHCB2) as key regulators.
  • The dataset offers a prioritized roadmap for mechanistic experiments to establish causality and translate findings into equine lactation health and management.

Cite This Article

APA
Liu L, Chen B, Kong M, Tian Y, Ma H, Cao H, Liu W. (2026). ATAC-seq and RNA-seq reveal key genes and pathways regulating lactation in the mammary gland of Yili horses. BMC Genomics. https://doi.org/10.1186/s12864-026-12840-6

Publication

BMC genomics
ISSN: 1471-2164
NlmUniqueID: 100965258
Country: England
Language: English

Researcher Affiliations

Liu, Lingling
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China. linglingliu1988@xjau.edu.cn.
Chen, Bin
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China.
Kong, Mengjiao
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China.
Tian, Yujie
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China.
Ma, Haiyu
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China.
Cao, Hang
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China.
Liu, Wujun
  • College of Animal Science, Xinjiang Agricultural University, Urumqi, 830052, China. wujunliu1026@xjau.edu.cn.

Grant Funding

  • 2023TSYCCX0033 / Tianshan Talent Program

Conflict of Interest Statement

Declarations. Ethics approval and consent to participate: This study aimed to investigate mammary gland tissues in horses, and the use of animals was justified by the lack of viable alternatives and minimized in accordance with the 3R principles. all mares were rendered unconscious by electrical stunning in accordance with the Chinese National Standard SN/T 4102 − 2015 “Animal welfare specification for horses during breeding, transport and slaughter”. Immediately after stunning, exsanguination was performed via severance of the carotid arteries and jugular veins, and death was confirmed prior to tissue collection. The protocol, involving the slaughter of six horses for tissue collection, was reviewed and approved by the animal welfare and ethics Committee of Xinjiang agricultural university (Approval No. 2024044). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

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