Areas of Interest
My lab is interested in understanding how gene expression is
regulated at the RNA level. In previous studies, we discovered a
novel family of human tumor antigens (HuR, HuD and HuC) that can
turn on gene expression by suppressing factors that silence
mRNA. Interest in these proteins continues, in collaboration
with Myriam Gorospe (NIH) and David Gillespie (Glasgow), we have
recently observed that HuR is regulated by CHK2 kinase, the
major mediator of DNA damage induced inhibition of cell
proliferation. These tumor antigens bind to specific elements
within mRNAs and displace silencing factors such as TTP and
AUF1. This high affinity interaction is mediated by two
classical ” RRM type” RNA binding domains. However, these
proteins contain a third RNA binding domain that we have found
is not required for binding to mRNA but is essential for the
suppression of silencing. Thus, the critical, yet mysterious
role of the third RNA binding domain of HuR is an important
focus of our current studies.
The other major interest in the lab is the mechanism of
action of human microRNAs. First discovered in C. Elegans, these
small RNAs guide protein cofactors to target mRNAs and silence
their expression. MicroRNAs are potent pleotropic effectors in
mammals since their targeted deletion in mice leads to profound
disease phenotypes such as cancer, cardiac perturbation and
immune deficiency. However, a current major challenge is to
understand how microRNAs engage their protein co-factors, select
their mRNA targets and silence expression. To study this at the
molecular level, we have established an in vitro silencing
system which utilizes recombinant Argonaute2, human let-7
microRNA and a model target mRNA.
The elements in human mRNA that are targeted by microRNAs are
remarkably polymorphic. Indeed, we have found that common human
sequence variants can modulate microRNA directed silencing of
expression. This observation suggests a novel paradigm by which
these variants may affect human behavior and susceptibility to
disease. Currently, we are studying variants that modulate
microRNA action in human behavioral genes (opioid receptors,
serotonin receptors, nicotinic receptors) and in genes (BRCA1)
whose silencing increases the susceptibility to breast and
ovarian cancer. The clinical implications of our studies on
functional germ line variants in BRCA1 mRNA are being pursued in
collaboration with Dr. Molly Brewer (Neag Cancer Center).
Lab Rotation Projects
Students who wish to formulate their own novel questions
about the roles of noncoding RNA in gene expression are
welcomed.
Selected Publications
Jensen KP, Covault J, Conner TS, Tennen H, Kranzler HR,
Furneaux HM. 2009 A common polymorphism in serotonin receptor 1B
mRNA moderates regulation by miR-96 and associates with
aggressive human behaviors. Molecular Psychiatry. 14 381-9
Salzman DW, Shubert-Coleman J, Furneaux H. (2007)
P68 RNA Helicase unwinds the human let-7 microRNA precursor
duplex and is required for let-7 directed silencing of gene
expression. JBC in press
Chakrabarty A, Tranguch S, Daikoku T, Jensen K, Furneaux H,
Dey SK. MicroRNA regulation of cyclooxygenase-2 during embryo
implantation. (2007) PNAS in press
Abdelmohsen K., Pullmann R., Jr., Lal, A., Kim, HH. Galban,S.,
Yang, X., Blethrow,J,, Shubert J., Gillespie, DA, Furneaux H.
and Gorospe, M. (2007) Regulation of SIRT1 Expression by
RNA-Binding Protein HuR: Role of Checkpoint Kinase Chk2
Molecular Cell, 25 543-57.
Adams, BD, Furneaux H, White, B. (2007) The micro-RNA miR-206
Targets the Human Estrogen Receptor and Represses ER mRNA and
Protein Expression in Breast Cancer Cell Lines. Molecular
Endocrinology 21 1132-47. rev. 3/09 |
