In the FTO obesity locus, which upstream regulator normally represses the enhancer controlling IRX3/IRX5 expression?

Question

BlackTom AI · Accepted Answer

ARID5B is a transcriptional repressor that binds the obesity-associated regulatory element in the FTO locus and normally suppresses the enhancer that drives IRX3 and IRX5 expression.

1. Relevant knowledge points and concepts
- The FTO obesity locus contains noncoding variants that alter a regulatory enhancer controlling the expression of the developmental transcription factors IRX3 and IRX5; increased IRX3/IRX5 expression shifts adipocyte precursors toward energy-storing white adipocytes.
- Upstream regulators (transcription factors) can repress or activate enhancers by binding DNA motifs; loss of a repressor or its binding increases enhancer activity and target gene expression.
- ARID5B (AT-rich interaction domain 5B) is a transcriptional regulator known to bind AT-rich sequences and act as a repressor at certain enhancers, including the FTO-associated enhancer.

2. Step-by-step reasoning
- The functional link established by genetic and molecular studies shows that the obesity-associated noncoding region in intron 1 of FTO acts as an enhancer for IRX3/IRX5.
- Investigations identified binding sites for ARID5B within this enhancer and demonstrated that ARID5B occupancy normally reduces enhancer activity.
- When ARID5B binding is disrupted (by risk allele or perturbation), repression is relieved, leading to increased IRX3/IRX5 expression and predisposition to adiposity.

3. Intermediate evidence steps
- Chromatin immunoprecipitation (ChIP) and reporter assays show ARID5B binding correlates with lower enhancer-driven reporter activity.
- Loss-of-function or diminished binding results in higher reporter expression and upregulation of IRX3/IRX5 in adipocyte models.

4. Why the correct answer is correct
- ARID5B directly represses the FTO-locus enhancer; this mechanistic role explains how changes at that site increase IRX3/IRX5 expression and influence adipocyte differentiation, linking genotype to phenotype.

5. Why other options are incorrect
- SORT1 and PCSK9 are genes involved in lipid metabolism but are not documented repressors of the FTO enhancer.
- FTO is the gene locus containing the enhancer but not the upstream repressor regulator.
- TCF21 is a transcription factor with roles in development but not identified as the repressive regulator of the IRX3/IRX5-controlling enhancer.

6. Conclusion
This evidence confirms ARID5B is the upstream regulator that normally represses the enhancer controlling IRX3/IRX5 expression, matching the provided answer: ARID5B.

In the FTO obesity locus, which upstream regulator normally represses the enhancer controlling IRX3/IRX5 expression?Single choice

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