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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...
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Novel and Haplotype Specific MicroRNAs Encoded by the Major Histocompatibility Complex.

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|March 3, 2018
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Summary
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Researchers identified 89 novel microRNA (miRNA) transcripts in the human Major Histocompatibility Complex (MHC), many linked to disease-associated variants and haplotypes, offering insights into genetic disease contributions.

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Area of Science:

  • Genomics and Molecular Biology
  • Human Genetics
  • RNA Biology

Background:

  • The Major Histocompatibility Complex (MHC) is crucial for human health and disease.
  • Many disease-associated genetic variants in the MHC are in non-coding regions, with unknown functional significance.
  • Understanding non-coding RNA transcripts in the MHC is key to deciphering the genetic basis of MHC-related diseases.

Purpose of the Study:

  • To characterize novel microRNA (miRNA) transcripts within the human MHC.
  • To investigate the biogenesis and functional loading of these novel miRNAs.
  • To explore the association of identified miRNAs with MHC haplotypes, single nucleotide polymorphisms (SNPs), and disease phenotypes.

Main Methods:

  • Deep RNA sequencing of two B lymphoblastoid cell lines with fully characterized MHC haplotypes.
  • Analysis of Dicer-dependent biogenesis and Argonaute complex loading for novel miRNA candidates.
  • In silico analysis to predict additional putative pre-miRNA encoding loci within the MHC.

Main Results:

  • Identification of 89 novel miRNA transcripts in the MHC.
  • Confirmation of Dicer-dependent biogenesis and Argonaute loading for 48 of these novel miRNAs.
  • Discovery of several miRNA transcripts unique to specific MHC haplotypes, overlapping common SNPs.
  • Association of 43 novel miRNA transcripts with linkage disequilibrium blocks containing disease-associated SNPs linked to 65 unique disease phenotypes.
  • In silico prediction of thousands of potential pre-miRNA encoding loci in the MHC.

Conclusions:

  • Novel miRNA transcripts within the MHC are identified, some with haplotype-specific expression and disease associations.
  • These novel miRNAs may contribute to the etiology of numerous MHC-associated diseases.
  • The MHC harbors a vast, largely uncharacterized repertoire of miRNA precursors with potential roles in diverse cellular contexts and developmental stages.