Maverick Science mag 2013-14

Immuno-histochemical staining showing the distribution of MLL1 along the line of blood vessels
(basement membrane) in the core of tumor tissue. CD31 is a well-known marker for angiogenesis.
DAPI staining shows the nucleus. Image courtesy of Subhrangsu Mandal.
MLL family of chromatin-modifying enzymes is a
major player in the proliferation of tumor cells, angiogenesis
and hypoxia signaling and antisensemediated
gene targeting to MLL led to a
suppression of tumor growth. This work revealed
a novel epigenetic mechanism of tumor cell signaling.
MLLs are novel targets for cancer therapy.”
Mandal hopes that this research will eventually
provide a new paradigm in antisense therapy and
the discovery of new epigenetic medicines.
In 2001, after over a decade of work,
scientists successfully completed the
first-ever “map” of the human
genome, the complete set of genetic
information for humans. This has
opened the door for scientific exploration
of subtle genetic influences on
many common diseases.
Another of Mandal’s current projects involves
non-coding RNAs and their roles in epigenetics and
disease. RNA is ribonucleic acid, a family of large
biological molecules that perform many important
roles in the coding, decoding, regulation, and expression
of genes. RNA joins with DNA to form nucleic
acids, which are essential for all known forms
of life. An epigenome is a layer of biochemical reactions
that turns genes on and off. It consists of
chemical compounds that modify the genome and
tell it how to behave.
“The human genome sequencing founded an
important milestone in today’s functional genomics
world and fueled biomedical research by providing
detailed nucleotide sequence information for protein
coding genes present in humans,” Mandal said.
“This helped in understanding the function of various
human genes, their transcriptional regulatory
network and roles in human diseases.”
It was found that only a tiny percentage of the
human genome encodes functional protein coding
genes, with the rest considered to be mostly nonfunctional,
or “junk DNA”. Subsequent studies suggested
that more than 80 percent of the genome
contains functional DNA elements that do not code
for proteins. These non-coding sequences include
DNA elements and sequences which code for transcripts
that are never translated into proteins.
These transcripts that are coded by the genome,
transcribed into RNA, but are not translated into
proteins are called non-coding RNAs (ncRNAs).
“Studies show that non-coding RNAs are critical
players in gene regulation, maintenance of genomic
integrity, cell differentiation, and development and
they are misregulated in various human diseases,”
Mandal said.
Mandal and his students are working with several
non-coding RNAs, studying their roles in chromatin
organization, gene regulation and diseases
while trying to identify novel ncRNAs. One is called
HOTAIR (for HOX antisense intergenic RNA),
which is located on chromosome 12. Studies from
Mandal’s lab have shown that HOTAIR is a key regulator
in gene silencing, interacting with various
gene silencing machineries and recruiting them to
the target gene.
“HOTAIR is overexpressed in breast cancer and
it is transcriptionally induced upon exposure estradiol
and expression is critical for cell viability and
growth, tumor invasiveness and metastasis,” Mandal
said. “Knockdown of HOTAIR expression resulted
in breast cancer cell death, indicating its
potential application in novel cancer therapy.”
Arunoday Bhan, a fourth-year doctoral student
in Mandal’s lab, is among those working on the
project. He says he is excited to be taking part in research
that could benefit millions of people.
“The data generated from our research will not
only aid in the formulation of therapies for cancer
treatment but also could identify potential molecular
targets that can be further developed as targets
for therapeutic drugs or as prognostic markers for
the identification of cancer at an early stage,” Bhan
said. “It makes me proud that I am contributing towards
the detailed understanding of the cancer
epigenome that in the future might save people’s
lives, or at least lengthen their life spans. I feel humbled
by the fact that the research carried out in our
lab would serve the community and society as a
whole.”
Paromita Deb, a second-year doctoral student,
is also part of the project, studying non-coding
RNAs and homeobox genes, which are a large family
of similar genes that direct the formation of
many body structures during early embryonic development.
“Homeobox genes are involved in developmentrelated
diseases and therefore, diagnosis of these
genes could be important to therapy,” Deb said.
“Dr. Mandal's innovative ideas have helped me sail
through a sea of experimental hardships. He has
always motivated me to work toward my goals.”
Mandal says it is an exciting time to be involved
in research which is showing how human genes
function and which could lead to breakthroughs in
methods of disease treatment and prevention.
“Biochemical and biomedical research has
reached a special stage, the ‘post genomic and
epigenomic era’,” he said. “The human genome has
been sequenced and now epigenomes are being
discovered. Recent projects discovered that ‘junk
DNA’ in the human genome is not really junk at all.
In fact, it is code for many non-coding RNA that
control the functionality of the whole genome.
These provide much deeper insight about how the
human genome is packaged, read and transcribed
into RNA and translated into protein.”
A
nother of Mandal’s ongoing
projects involves assessing
how various chemicals
found in the environment
can disrupt the ability of the
body’s endocrine system to
function properly. The endocrine
system is a collection
of glands that secrete
chemical messages, called hormones, to organs
throughout the body.
“Almost everything in your body is controlled
by hormones,” Mandal said. “Hormones control
26 Maverick Science 2013-14