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Genome-wide binding patterns of thyroid hormone receptor beta.

Ayers S, Switnicki MP, Angajala A, Lammel J, Arumanayagam AS, Webb P - PLoS ONE (2014)

Bottom Line: In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system.There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks.We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions.

View Article: PubMed Central - PubMed

Affiliation: The Methodist Hospital Research Institute, Genomic Medicine Program, Houston, Texas, United States of America.

ABSTRACT
Thyroid hormone (TH) receptors (TRs) play central roles in metabolism and are major targets for pharmaceutical intervention. Presently, however, there is limited information about genome wide localizations of TR binding sites. Thus, complexities of TR genomic distribution and links between TRβ binding events and gene regulation are not fully appreciated. Here, we employ a BioChIP approach to capture TR genome-wide binding events in a liver cell line (HepG2). Like other NRs, TRβ appears widely distributed throughout the genome. Nevertheless, there is striking enrichment of TRβ binding sites immediately 5' and 3' of transcribed genes and TRβ can be detected near 50% of T3 induced genes. In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system. Canonical TRE half-sites are present in more than 90% of TRβ peaks and classical TREs are also greatly enriched, but individual TRE organization appears highly variable with diverse half-site orientation and spacing. There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks. We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions. Better understanding of genomic context of TR binding sites will help us determine why TR regulates genes in different ways and determine possibilities for selective modulation of TR action.

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Definition of TRE Consensus.A. Consensus sequence with similarity to the classic TRβ binding half-site discovered by analysis of top 150 peaks in BioChIP analysis. B. The previously defined TRβ consensus obtained from analysis of more than 30 published target gene regulatory elements is shown for comparison at right.
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pone-0081186-g005: Definition of TRE Consensus.A. Consensus sequence with similarity to the classic TRβ binding half-site discovered by analysis of top 150 peaks in BioChIP analysis. B. The previously defined TRβ consensus obtained from analysis of more than 30 published target gene regulatory elements is shown for comparison at right.

Mentions: Investigation of sequence composition of genomic regions bound by TRβ revealed elements that resembled the typical TRE consensus within the peaks. A query of the top 150 bound peaks revealed high prevalence of a single TRE half sites (TGAGGTCA) (Fig. 5A), distinct from a previous consensus derived from analysis of a smaller number of TREs which contained two detectable half sites spaced by four bases (Fig. 5B, 28). Interestingly, this previous study also suggested that the paired G residues (TGAGGTCA) were the most important determinants of TRβ binding [30]. While our analysis confirmed that these nucleotides are indeed highly represented, it also revealed higher representation of other nucleotides within the half site than previously defined (TGAGGTCA).


Genome-wide binding patterns of thyroid hormone receptor beta.

Ayers S, Switnicki MP, Angajala A, Lammel J, Arumanayagam AS, Webb P - PLoS ONE (2014)

Definition of TRE Consensus.A. Consensus sequence with similarity to the classic TRβ binding half-site discovered by analysis of top 150 peaks in BioChIP analysis. B. The previously defined TRβ consensus obtained from analysis of more than 30 published target gene regulatory elements is shown for comparison at right.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928038&req=5

pone-0081186-g005: Definition of TRE Consensus.A. Consensus sequence with similarity to the classic TRβ binding half-site discovered by analysis of top 150 peaks in BioChIP analysis. B. The previously defined TRβ consensus obtained from analysis of more than 30 published target gene regulatory elements is shown for comparison at right.
Mentions: Investigation of sequence composition of genomic regions bound by TRβ revealed elements that resembled the typical TRE consensus within the peaks. A query of the top 150 bound peaks revealed high prevalence of a single TRE half sites (TGAGGTCA) (Fig. 5A), distinct from a previous consensus derived from analysis of a smaller number of TREs which contained two detectable half sites spaced by four bases (Fig. 5B, 28). Interestingly, this previous study also suggested that the paired G residues (TGAGGTCA) were the most important determinants of TRβ binding [30]. While our analysis confirmed that these nucleotides are indeed highly represented, it also revealed higher representation of other nucleotides within the half site than previously defined (TGAGGTCA).

Bottom Line: In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system.There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks.We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions.

View Article: PubMed Central - PubMed

Affiliation: The Methodist Hospital Research Institute, Genomic Medicine Program, Houston, Texas, United States of America.

ABSTRACT
Thyroid hormone (TH) receptors (TRs) play central roles in metabolism and are major targets for pharmaceutical intervention. Presently, however, there is limited information about genome wide localizations of TR binding sites. Thus, complexities of TR genomic distribution and links between TRβ binding events and gene regulation are not fully appreciated. Here, we employ a BioChIP approach to capture TR genome-wide binding events in a liver cell line (HepG2). Like other NRs, TRβ appears widely distributed throughout the genome. Nevertheless, there is striking enrichment of TRβ binding sites immediately 5' and 3' of transcribed genes and TRβ can be detected near 50% of T3 induced genes. In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system. Canonical TRE half-sites are present in more than 90% of TRβ peaks and classical TREs are also greatly enriched, but individual TRE organization appears highly variable with diverse half-site orientation and spacing. There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks. We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions. Better understanding of genomic context of TR binding sites will help us determine why TR regulates genes in different ways and determine possibilities for selective modulation of TR action.

Show MeSH
Related in: MedlinePlus