RNA-Seq reveals previously unsuspected properties for two distinct categories of regulatory RNAs

The production of microRNA isoforms in human tissues depends on a person’s gender, population origin, and race as well as on tissue, disease and disease subtype

Researchers at Thomas Jefferson University previously reported that miRNA isoforms in healthy individuals change as a function of people’s gender, population, and race.

rna-seq

Loher P, Londin ER, Rigoutsos I. (2014) IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies. Oncotarget 5(18):8790-802. [article]

The researchers have now extended these results to the disease context (breast cancer, in particular) and, by analyzing data from hundreds or individuals, have shown that:

  1. individuals belonging to the same gender produce different miRNA isoforms in the normal state of the same tissue as a function of race
  2. patients with the same disease subtype who belong to the same gender produce different miRNA isoforms in the disease state as a function of race
  3. in a given tissue, miRNA isoform profiles change with disease subtype (even for people belonging to the same race)
  4. in a given tissue, miRNA isoforms exhibit preferential Argonaute loading as a function of tissue sub-type, and
  5. in a given tissue, miRNA isoforms from the same miRNA locus can have very distinct targetomes

rna-seq

Luminal A and Luminal B intrinsic subtypes have distinct isomiR profiles.

In other words, going forward, it will not be sufficient to state that one is studying “miR–183 in e.g. breast cancer” Instead, one would need to say I am studying “this specific isoform of miR–183 in this cell type and in patients of this race (gender, and population)”.

Telonis AG, Loher P, Jing Y, Londin E, Rigoutsos I. (2015) Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity. Nucleic Acids Res 43(19):9158-75. [article]

The production of tRNA fragments in human tissues depends on a person’s gender, population origin, and race as well as on tissue, disease and disease subtype

Next-gen sequencing revealed several years ago that mature tRNAs can give rise to four structural categories of short tRNA fragments or tRFs: 5´-halves, 3´-halves, 5´-tRFs and 3´-tRFs. By analyzing hundreds of healthy individuals and patients, the researchers showed that:

  1. mature tRNAs also make a fifth, previously unreported category of short RNAs that we refer to as “internal tRFs” or i-tRFs
  2. all five structural categories of tRFs are constitutive across individuals
  3. mitochondrial tRNAs produce fragments just like their unclearly-encoded counterparts
  4. in the same tissue, mitochondrial tRNAs are fragmented differently than their nuclearly-encoded counterparts
  5. in a given tissue, the composition and abundance profiles of tRNA fragments change as a function of
    1. a person’s gender, population origin, and race
    2. tissue, disease, and disease sub-type.
    3. analogously to miRNAs and miRNA isoforms, tRNA fragments are loaded on Argonaute and thus enter the RNA interference pathway as well.

rna-seqtRFs abundances are specific to tissue- and tissue-state.

In other words, going forward, it will be necessary to take into account all of the short RNAs that are produced by mature tRNAs as they too have regulatory roles (akin to those of miRNAs).

Telonis AG, Loher P, Honda S, Jing Y, Palazzo J, Kirino Y, Rigoutsos I. (2015) Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies. Oncotarget 6(28):24797-822. [article]

The above two lines of research activity have direct implications for Precision Medicine and suggest that not only do we need to explicitly incorporate these new molecules (miRNA isoforms and tRNA fragments) in all future studies of post-transcriptional regulatory mechanisms that underlie the onset and progression of disease but to also begin recognizing differences in the regulatory molecules that exist in people belonging to different genders, different populations, and different races.

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