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SATB1 promotion of trophoblast stem cell renewal through regulation of threonine dehydrogenase
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-10-01 , DOI: 10.1016/j.bbagen.2020.129757
Kaiyu Kubota 1 , Khursheed Iqbal 1 , Michael J Soares 2
Affiliation  

Background

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.

Methods

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.

Results

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.

Conclusions

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.

General significance

Regulatory pathways controlling TS cell dynamics dictate the functionality of the placenta, pregnancy outcomes, and postnatal health.



中文翻译:

SATB1通过调节苏氨酸脱氢酶促进滋养层干细胞更新

背景

滋养层干细胞 ( TS ) 更新和分化是胎盘形成的重要过程。富含 AT 的特殊结合蛋白 1 ( SATB1 ) 是 TS 细胞干状态的关键调节因子。在这项研究中,我们确定了 SATB1 下游目标并研究了它们的作用。

方法

在表达对照或Satb1短发夹 RNA ( shRNA ) 的Rcho-1 TS 细胞中进行 RNA 测序分析,以鉴定候选 SATB1 靶标。通过逆转录定量聚合酶链反应验证差异调节的转录本。使用功能丧失方法研究了SATB1 的靶标 L-苏氨酸 3-脱氢酶 ( TDH ) 在调节滋养层细胞发育中的作用。

结果

在 SATB1 敲低 TS 细胞中差异调节的转录物中,下调的转录物已知影响 TS 细胞干状态,上调的转录物是滋养层细胞分化的特征。Tdh表达对 SATB1 失调反应灵敏。Tdh表达在 TS 细胞干状态下较高,并随着 TS 细胞分化而降低。用 TDH 抑制剂或 TDH 特异性 shRNA 处理 Rcho-1 TS 细胞可抑制细胞增殖,减弱 TS 细胞干状态相关转录物的表达,并升高滋养层细胞分化相关转录物的表达。TDH 破坏降低了 TS 细胞集落大小、Cdx2表达和囊胚生长。

结论

我们的研究结果表明,SATB1 对 TS 细胞维持的作用至少部分是通过 TDH 的调节和作用介导的。

一般意义

控制 TS 细胞动态的调节途径决定胎盘的功能、妊娠结局和产后健康。

更新日期:2020-10-06
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