Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome
Bibliographic record
Abstract
The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains incompletely characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome (MDS) and myeloid leukemia of Down Syndrome, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility determines GATA1 cistrome specificity and lineage fate decisions. To understand the connection between chromatin accessibility and GATA1, we comprehensively studied erythropoiesis in Stag2∆ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid differentiation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Despite unchanged Gata1 expression, Gata1 occupancy was reprogrammed from erythroid to megakaryocyte targets with Fli1 motifs enriched at Stag2∆ Gata1 binding sites. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays, which was partially reversed with Fli1 knockdown. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study establishes chromatin accessibility as a determinant of transcription factor binding specificity, revealing an accessibility-driven Gata1 retargeting mechanism underlying MDS dyserythropoiesis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".