(RESEARCH PROJECT II) The trophoblast lineage arises early in embryonic development through a complex interaction of transcriptional and epigenetic regulators controlling key signaling pathways. Trophoblast stem (TS) cells possess the capacity to self-renew and differentiate into specialized trophoblast cell populations required for the establishment and maintenance of pregnancy. However, the epigenetic modifications, and the hierarchy of the transcriptional regulators, which determine trophoblast lineage, maintain the trophoblast cell stem state and regulate the multilineage differentiation are poorly understood. We have identified two related proteins, special AT-rich sequence-binding protein 1 (SATB1) and SATB2, which can act as chromatin organizers and transcriptional regulators, contribute to both the maintenance and expansion of TS cells and the inhibition of trophoblast differentiation. SATB proteins are proposed to play a key role in the regulatory network controlling trophoblast development. In this research project, three specific aims are proposed: 1) to investigate the role of SATB proteins in the regulation of trophoblast lineage determination;2) to establish the position of SATB proteins in the hierarchy of regulators controlling the TS cell stem state;3) to evaluate the in vivo role of SATB proteins in trophoblast development. The proposed study will utilize in vitro rodent and human stem cell models and mouse mutagenesis to explore the role of SATB proteins in regulating the trophoblast development. Genome wide analysis of transcriptional and epigenetic modifications will be coupled to transcriptome analysis to identify upstream regulators of SATB expression and downstream targets of SATB action. This research investigation will reveal novel properties of trophoblast stem cell regulation and expand our understanding of the disorders associated with early pregnancy loss.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
1P01HD079363-01A1
Application #
8743038
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
DUNS #
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Chakraborty, Damayanti; Cui, Wei; Rosario, Gracy X et al. (2016) HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia. Proc Natl Acad Sci U S A 113:E7212-E7221
Soares, Michael J; Vivian, Jay L (2016) Tipping the balance toward trophoblast development. Proc Natl Acad Sci U S A 113:5144-6
Imakawa, Kazuhiko; Dhakal, Pramod; Kubota, Kaiyu et al. (2016) CITED2 modulation of trophoblast cell differentiation: insights from global transcriptome analysis. Reproduction 151:509-16
Carey, Timothy S; Cao, Zubing; Choi, Inchul et al. (2015) BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation. Mol Cell Biol 35:4158-69
Kubota, Kaiyu; Kent, Lindsey N; Rumi, M A Karim et al. (2015) Dynamic Regulation of AP-1 Transcriptional Complexes Directs Trophoblast Differentiation. Mol Cell Biol 35:3163-77
Renaud, Stephen J; Chakraborty, Damayanti; Mason, Clifford W et al. (2015) OVO-like 1 regulates progenitor cell fate in human trophoblast development. Proc Natl Acad Sci U S A 112:E6175-84
Cao, Zubing; Carey, Timothy S; Ganguly, Avishek et al. (2015) Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage. Development 142:1606-15
Soares, Michael J (2014) Embryo implantation - coordination of maternal and embryonic adaptations. Int J Dev Biol 58:71-4
Soares, Michael J; Chakraborty, Damayanti; Kubota, Kaiyu et al. (2014) Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy. Int J Dev Biol 58:247-59
Knott, Jason G; Paul, Soumen (2014) Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation. Reproduction 148:R121-36