Jefferson University. US: According to the public databases, there are currently approximately
1,900 locations in the human genome that produce microRNAs (miRNAs),
the small and powerful non-coding molecules that regulate numerous
cellular processes by reducing the abundance of their targets.
New
research published in the Proceedings of the National Academy of Sciences (PNAS)
this week adds another roughly 3,400 such locations to that list. Many
of the miRNA molecules that are produced from these newly discovered
locations are tissue-specific and also human-specific. The finding has
big implications for research into how miRNAs drive disease.
“By analyzing human deep-sequencing data, we discovered many new
locations in the human genome that produce miRNAs. Our findings
effectively triple the number of miRNA-generating loci that are now
known” says Isidore Rigoutsos, Ph.D., Director of the Computational Medicine Center
at Thomas Jefferson University, who led the study. “This new
collection will help researchers gain insights into the multiple roles
that miRNAs play in various tissues and diseases.”
For nearly three years, the team collected and sequenced RNA from
dozens of healthy and diseased individuals. The samples came from
pancreas, breast, platelets, blood, prostate, and brain. To their
collection they also added publicly available data eventually reaching
more than 1,300 analyzed samples representing 13 human tissue types.
Their analyses uncovered 3,356 new locations in the human genome that
generate over 3,700 previously undescribed miRNAs.
For a handful of the 13 tissues they studied, the team also had
access to information describing miRNA association with Argonaute, an
essential protein member of the regulatory complex that enables miRNA to
interact with their targets. They found that 45 percent of the newly
discovered miRNAs were in fact associated with Argonaute, a further
indication that these molecules are involved in gene regulation. “We
anticipate that many more of the newly discovered miRNAs will be found
loaded on Argonaute as additional such data become available for the
other tissues,” says Eric Londin, Ph.D., an Assistant Professor and
co-first author together with Phillipe Loher, M.S., a computational
biologist and software engineer, both members of Jefferson’s
Computational Medicine Center.
One of the key design choices that the team made was to not limit
their search to conserved genomic sequences, i.e. to only those
sequences that are shared across multiple organisms. Instead the
researchers scanned the genome much more broadly. “Advances in
sequencing technology of the last several years made it easier to
generate more data, from more tissues, and do so faster,” says Dr.
Rigoutsos who is also a researcher at the Sidney Kimmel Cancer Center
at Thomas Jefferson University. “Investigating the alluring possibility
that miRNAs with important roles might exist only in humans was within
reach. And this is what we set out to do.”
Of the new molecules, 56.7 are specific to humans and most of them
(94.4 percent) are found only in primates. Because of this
organism-specificity these RNA molecules are involved in regulatory
events that are absent from model organisms such as mouse and the fruit
fly.
Tissue-specificity is another important characteristic of these new
miRNAs. It means that these molecules are behind molecular events that
are present in a single tissue, or in only a few tissues. Some of these
molecules could potentially prove useful as novel tissue-specific
disease biomarkers.
The tissue- and primate-specificity of the new molecules are expected
to have important implications for the community’s attempts to
understand the causes of diseases. A first step in that direction
requires the identification and validation of the targets for each of
these 3,707 new miRNAs. To assist in these efforts, the team generated
computational predictions of each miRNA’s putative targets that are
available from the Computational Medicine Center’s website.
This research was supported by a grant from the W. M. Keck
Foundation, the Hirshberg Foundation for Pancreatic Cancer Research, the
Tolz Foundation Weizmann Institute of Science-Thomas Jefferson
University Collaboration Program, a Pilot Project Award by the NIH
Autoimmune Centers of Excellence (2U19-AI056363-06/2030984) the NIH-NCI
Cancer Center Core grant (P30CA56036), by TJU Institutional funds. Study
authors were also supported by the following grants: NIH grant
CA140424, Lifespan/Tufts/Brown Center for AIDS Research (P30 AI042853),
NIH Grants AG042419, NS085830 and AG028383, NIH/NIAMS grant R01 AR
19616, CLL Global Research Foundation, by a sister Institution Network
Foundation MDACC-DKFZ grant on CLL, the Laura and John Arnold
Foundation, the RGK Foundation and the Estate of C.G. Johnson Jr, the
Jefferson Pancreas, Biliary and Related Cancer Center, grant HL102482
from the Heart, Lung and Blood Institute of the National Institute of
Health, the PA CURE grant, NIH grant CA099996, NIH grant GM106047, and
DOD grant PC094507.
Paper reference: E.R. Londin, P. Loher, et al., “Analysis of 13 cell types reveals evidence for the
expression of numerous novel primate- and tissue-specific microRNAs,” PNAS, DOI 10.1073/pnas.1420955112, 2015.