Disturbed function of TBL1X has a differential effect on T3-regulated gene expression in two human liver cell models

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Mutations in TBL1X, a component of the NCOR1/SMRT corepressor complex, are associated with X-linked central congenital hypothyroidism and hearing loss.
• The precise function of TBL1X in thyroid hormone (TH) action remains unclear.
• This research investigates TBL1X's role in regulating gene expression influenced by triiodothyronine (T3).

Purpose of the Study:

• To elucidate the role of TBL1X in T3-regulated gene expression.
• To compare the effects of TBL1X downregulation and a specific mutation (N365Y) on TH target genes in human liver cells.

Main Methods:

• Utilized a human hepatoma cell line (HepG2) with TBL1X downregulated via siRNA.
• Employed human-induced pluripotent stem cell-derived hepatocytes (iHeps) from individuals with a TBL1X N365Y mutation.
• Measured T3-regulated gene expression using quantitative PCR (qPCR) after T3 stimulation.

Main Results:

• In HepG2 cells, TBL1X downregulation led to increased KLF9, CPT1A, and PCK1 mRNA and decreased DIO1 mRNA expression following T3 stimulation.
• Hemizygous TBL1X N365Y iHeps showed reduced expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to heterozygous cells.
• KLF9 and HMGCS2 expression remained unchanged in TBL1X N365Y iHeps.

Conclusions:

• TBL1X downregulation and the N365Y variant exhibit distinct effects on T3-regulated gene expression in different cellular contexts.
• These findings suggest TBL1X plays a context-dependent role in thyroid hormone action.