Hierarchical enhancers 1 confer the temporal and partially compensatory transcriptional regulation of Nkx2-5 during heart development
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ABSTRACT:
PROVIDER: PRJNA552476 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10310085_1.fastq.gz | Fastqsanger.gz | |||
| SRR10310085_2.fastq.gz | Fastqsanger.gz | |||
| SRR10310086_1.fastq.gz | Fastqsanger.gz | |||
| SRR10310086_2.fastq.gz | Fastqsanger.gz | |||
| SRR10310087_1.fastq.gz | Fastqsanger.gz |
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Project description:We comprehensively interrogate enhancers U1 and U2 in controlling Nkx2-5 transcription during heart development. Serial genomic deletions in mice reveal a functional hierarchy of U1 and U2 as evidenced by stage-dependent phenotypic variations. Specifically, U1 and U2 function redundantly to confer Nkx2-5 expression at early stages, but U2 instead of U1 supported its expression at later stages of heart chamber formation and maturation. Combined deletions markedly reduce Nkx2-5 dosage as early as E7.5, despite being largely reinstated two days later, displaying heart malformations with precocious differentiation of cardiac progenitors. Together, we propose a model that the temporal and partially compensatory regulatory function of two enhancers dictates a TF?s dosage and specificity during development.
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Project description:NKL homeobox genes encode transcription factors which impact normal development and hematopoietic malignancies if deregulated. Recently, we established a NKL-code which describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL-genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6 and SOX7. SiRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1 and SIX5, and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte-erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating megakaryocytic and erythroid differentiation processes, and thereby driving formation specific AML subtypes.
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