Methylation of promoters of microRNAs and their host genes in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are a group of hematopoietic malignancies characterized by ineffective hematopoiesis. Recently, we identified MDS-associated microRNAs (miRNAs) that are down-regulated in MDS. This study examines possible explanations for that observed down-regulation of miRNA expression in MDS. Since genomic losses are insufficient to explain the down-regulation of all our MDS-associated miRNAs, we explored other avenues. We demonstrate that these miRNAs are predominantly intragenic, and that, in many cases, they and their host genes are expressed in a similar pattern during myeloid maturation, suggesting their co-regulation. This co-regulation is further supported by the down-regulation of several of the host genes in MDS and increased methylation of the shared promoters of several miRNAs and their respective host genes. These studies identify a role of hypermethylation of miRNA promoters in the down-regulation of MDS-associated miRNAs, unifying research on miRNAs in MDS and epigenetic regulation in MDS into a common pathway.

Keywords::

• Myelodysplastic syndrome
• microRNAs
• hypermethylation
• host genes
• myeloid maturation

Acknowledgements

We thank Dr. Christine Eischen for her thoughtful reading of the manuscript and Drs. Adam Seegmiller and Mary Ann Thomspon Arildsen for additional graphical and statistical suggestions. We also gratefully acknowledge the early assistance in the mining of published methylation data which was performed by Dr. Maria Figueroa, although that work is not specifically cited in this research.

This study was supported by the Doris Duke Charitable Foundation, Clinical Scientist Development Award (A.S.K.), CTSA grant UL1 RR024975 from NCRR/NIH (A.S.K.), American Cancer Society Institutional Research Grant #IRG-58-009-51 (A.S.K.) and the CCSG 5P30 CA068485 (histology).

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.