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Project description for A*STAR-Imperial Partnership (AIP) PhD Programme
Title: Understanding the cross-regulatory feedback circuit between HNF1α and HNF4α in determining pancreatic β cell
function
Heterozygous mutations in hepatocyte nuclear factor 1A (HNF1A) and HNF4A are known to cause maturity onset
diabetes of the young (MODY) (Yamagata et al., 1996a; Yamagata et al., 1996b). In fact, the pancreatic β cell phenotype
in MODY1 (HNF4A) and MODY3 (HNF1A) subjects is very similar (Byrne et al., 1995; Byrne et al., 1996). Hnf1α has been
demonstrated to be important for Hnf4α gene expression in pancreatic β cells (Boj et al., 2001; Shih et al., 2001).
Conversely, Hnf4α has also been reported to be important for Hnf1α gene expression in pancreatic β cells (Gragnoli et al.,
1997; Wang et al., 2000). Therefore, it is increasingly accepted that there is a positive cross-regulatory feedback circuit
between Hnf1α and Hnf4α in the regulation of pancreatic β cell function and its glucose-sensing machinery (Figure 1)
(Ferrer, 2002; Hansen et al., 2002). However to date, it is still largely unclear how the loss of a Hnf1α allele affects the
expression of Hnf4α and vice versa, in pancreatic β cells. Whilst Hnf1α and Hnf4α probably control a common genetic
program in pancreatic β cells, we do not yet know their global molecular targets in human pancreatic progenitors and
mature β cells, and if they are indeed the same molecular targets. Furthermore, it is yet unclear how a single autosomal
dominant mutation in HNF1A and/or HNF4A predisposes MODY subjects to develop diabetes only in the second to fourth
decade of life.
In this project, we seek to understand this intricate cross-regulatory feedback circuit between Hnf1α and Hnf4α which
ultimately determines pancreatic β cell function (Figure 1). Our scientific approach would include the use of:
1) Pancreatic β cells derived from MODY1 and MODY3 human induced pluripotent stem cells (hiPSCs) to study the
molecular interactions between HNF4A and HNF1A in determining human pancreatic β cell function (Teo et al.,
2014; Teo et al., 2013a; Teo et al., 2013b),
2) EndoC-bH1 and EndoC-bH2 human pancreatic β cell lines (Ravassard et al., 2011; Scharfmann et al., 2014) in
which the expression of HNF1A and HNF4A will be perturbed to understand the impact of their inter-regulatory
relationships on pancreatic β cell function, and
3) Numerous Hnf1α and Hnf4α-relevant cell lines and reagents generated by the Ferrer Lab.
Figure 1. Postulated switch positions of the pancreatic
Hnf1α/Hnf4α circuitry. The loss of one Hnf1α or Hnf4α
allele results in circuit inactivation, thereby affecting the
downstream pancreatic β cell gene function network
(Ferrer, 2002).
Through this collaborative project between the Teo Lab and Ferrer Lab, we seek to understand the following:
1) What are the molecular targets of HNF1A and HNF4A in human pancreatic progenitors and β cells?
2) How can a single mutation in one HNF1A and/or HNF4A allele perturb the whole pancreatic transcriptional
network and affect pancreatic β cell function?
3) Does HNF1A directly regulate the gene expression of HNF4A (and vice versa) in human pancreatic progenitors
and pancreatic β cells?
4) What are the molecular/epigenetic triggers which inactivate the Hnf1α/Hnf4α bistable circuit?
By unravelling the mechanism behind this cross-regulatory feedback circuitry between Hnf1α and Hnf4α, we will gain
significant insights into the glucose-sensing machinery of pancreatic β cells. The ability to improve the glucose-sensing
function of pancreatic β cells is therapeutically relevant to the insulin-resistant state in type 2 diabetes patients.
Contact Information:
Adrian Kee Keong TEO, Ph.D.
([email protected])
Junior Investigator, IMCB, A*STAR
Adjunct Assistant Professor, SBS, NTU
Adjunct Assistant Professor, Dept of Biochemistry,NUS
Website: http://www.imcb.a-star.edu.sg/php/iji-at.php;
www.adrianteolab.com
Professor Jorge FERRER, M.D., Ph.D.
([email protected])
Chair in Genetics and Medicine, Imperial College London
Head, Section of Epigenomics and Disease
Website: https://www.google.com.sg/webhp?sourceid=chromeinstant&rlz=1C1VFKB_enSG604SG604&ion=1&espv=2&ie=UT
F-8#q=jorge%20ferrer
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References
Boj, S.F., Parrizas, M., Maestro, M.A., and Ferrer, J. (2001). A transcription factor regulatory circuit in differentiated
pancreatic cells. Proc Natl Acad Sci U S A 98, 14481-14486.
Byrne, M.M., Sturis, J., Fajans, S.S., Ortiz, F.J., Stoltz, A., Stoffel, M., Smith, M.J., Bell, G.I., Halter, J.B., and Polonsky,
K.S. (1995). Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on
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