The role of chromatin in the transcriptional regulation of Hoxd4 during hindbrain development and neural differentiation /
Bibliographic record
Abstract
Mammalian Hox genes encode a highly conserved family of homeodomain-containing transcription factors that play a crucial role in specifying regional identity and embryonic patterning. Thirty-nine Hox genes are organized into four clusters on different chromosomes each containing up to eleven genes. Importantly, there is a correlation between the genomic location of a specific Hox gene within a cluster and its time and functional domain of expression during development, a phenomenon termed "colinearity". Altering normal Hox expression results in homeotic transformations and malformation, establishing the biological relevance of this tightly controlled expression pattern. Given the integral role of chromatin remodeling in gene regulation, colinear Hox gene activation could be explained in part by successive 3' to 5' conversion from closed to open chromatin along the length of a Hox cluster. We investigated the role of chromatin in regulating Hoxd4, a member of Hox paralog group 4, which is expressed in the CNS with an anterior boundary at r6/7. Previous studies in our laboratory mapped a 3' neural enhancer containing a critical retinoic acid response element absolutely necessary for Hoxd4 expression in the CNS. Moreover, transcripts originating from the P1 proximal promoter are more active in anterior domains of Hoxd4 expression and are responsive to the 3' neural enhancer. We used chromatin immunoprecipitation to detect chromatin changes at the Hoxd4 locus during neurogenesis in P19 cells and embryonic day (E) 8.0 and E 10.5 mouse embryos. In Chapter II, we show that during Hoxd4 induction in both systems, histone modifications typical of transcriptionally active chromatin occur first at the 3' neural enhancer, followed by the promoter. Moreover, the sequential distribution of histone modifications between E8.0 and E10.5 is consistent with a spreading of open chromatin starting with the enhancer, followed by successively more 5' intervening sequences, and culminating at the promoter. In Chapter III, we identify components of the Hoxd4 P1 promoter directing expression in neurally differentiating P19 cells. Our results show that three nucleosomes are positioned at the P1 promoter and are subsequently remodeled into an open chromatin state upon RA-induced Hoxd4 transcription. Moreover, an autoregulatory element was shown to recruit HOXD4 and its cofactor P13X1, and to positively regulate Hoxd4 expression. Conversely, YY1 binds to an inter-nucleosomel linker and represses Hoxd4 transcription before and during transcriptional activation, while the Polycomb Group protein member MEL 18 is co-recruited with YY1 only in undifferentiated P19 cells. In Chapter IV, we discuss the role of sequential chromatin opening in regulating Hox gene expression, and more specifically in controlling transcriptional initiation from P1. Finally, we discuss the consequences of transcription factor binding to P1, and the transcriptional characteristics of P1 that are crucial for regulating Hoxd4 transcription.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".