SATB1 promotion of trophoblast stem cell renewal through regulation of threonine dehydrogenase

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 1; p. 129757
• Main Authors: Kubota, Kaiyu, Iqbal, Khursheed, Soares, Michael J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2021
• Subjects: Alcohol Oxidoreductases - metabolism; Animals; Cell Line; Cell Self Renewal; Homeodomain Proteins - metabolism; Placenta; Rats; Rats, Sprague-Dawley; SATB1; Stem Cells - cytology; Stem Cells - metabolism; Threonine dehydrogenase; Trophoblast stem cells; Trophoblasts - cytology; Trophoblasts - metabolism; Placenta; SATB1; Trophoblast stem cells; Threonine dehydrogenase
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129757

Trophoblast stem (TS) cell renewal and differentiation are essential processes in placentation. Special AT-rich binding protein 1 (SATB1) is a key regulator of the TS cell stem state. In this study, we identified SATB1 downstream targets and investigated their actions. RNA-sequencing analysis was performed in Rcho-1 TS cells expressing control or Satb1 short hairpin RNAs (shRNAs) to identify candidate SATB1 targets. Differentially regulated transcripts were validated by reverse transcription-quantitative polymerase chain reaction. The role of a target of SATB1, L-threonine 3-dehydrogenase (TDH), in the regulation of trophoblast cell development was investigated using a loss-of-function approach. Among the differentially regulated transcripts in SATB1 knockdown TS cells, were downregulated transcripts known to affect the TS cell stem state and upregulated transcripts characteristic of trophoblast cell differentiation. Tdh expression was exquisitely responsive to SATB1 dysregulation. Tdh expression was high in the TS cell stem state and decreased as TS cells differentiated. Treatment of Rcho-1 TS cells with a TDH inhibitor or a TDH specific shRNA inhibited cell proliferation and attenuated the expression of TS cell stem state-associated transcripts and elevated the expression of trophoblast cell differentiation-associated transcripts. TDH disruption decreased TS cell colony size, Cdx2 expression, and blastocyst outgrowth. Our findings indicate that the actions of SATB1 on TS cell maintenance are mediated, at least in part, through the regulation and actions of TDH. Regulatory pathways controlling TS cell dynamics dictate the functionality of the placenta, pregnancy outcomes, and postnatal health. •Trophoblast stem cell expansion and differentiation are essential for placentation.•SATB1 promotes maintenance of the trophoblast stem cell stem state.•SATB1 regulates TDH expression in trophoblast stem cells.•TDH mediates some of the actions of SATB1 on trophoblast stem cells.