Upstream regulation of DLK1-DIO3 locus in hematopoiesis and pediatric leukemia

Non-coding RNAs (ncRNAs) recently emerged as central regulators of chromatin and gene expression, posing a novel window for targeted therapies in pediatric acute megakaryoblastic leukemia (AMKL). In our ncRNA expression atlas of the human hematopoietic system, we uncovered specific and coordinated expression of the DLK1-DIO3 locus in megakaryocytes and AMKL, which is essential of for promoting megakaryocytic differentiation, but also leukemic growth. To determine how expression of the DLK1-DIO3 locus is controlled, we performed several techniques elucidating different regulatory layers. Using bisulphite sequencing, a significant correlation between MEG3 expression and methylation of a CpG island downstream of the first exon of MEG3 was found, which displayed enhancer/promoter activity. CUT&RUN for key megakaryocytic transcription factors revealed increased binding of oncogenic GATA1s on several genomic locations upstream of DLK1 and MEG3. Overall, our study is the first step towards understanding the regulation of the DLK1-DIO3 locus in AMKL and normal hematopoiesis.

Publication History

Article published online:
17 May 2022