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A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes.

Cook DJ, Patra B, Kuttippurathu L, Hoek JB, Vadigepalli R - Front Physiol (2015)

Bottom Line: We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy.These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns.Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University Philadelphia, PA, USA ; Department of Chemical and Biomolecular Engineering, University of Delaware Newark, DE, USA.

ABSTRACT
Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-κB) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-κB binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-κB through categorizing NF-κB binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-κB binding by relating the temporal response profile to differential gene expression. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-κB also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-κB regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.

No MeSH data available.


Related in: MedlinePlus

Distance to transcription start site (TSS) at each time measured post-PHx. At 1 h post-PHx, the peak distance to TSS appears to decrease with more NF-κB binding close to the regulated gene both upstream and downstream.
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Figure 1: Distance to transcription start site (TSS) at each time measured post-PHx. At 1 h post-PHx, the peak distance to TSS appears to decrease with more NF-κB binding close to the regulated gene both upstream and downstream.

Mentions: NF-κB is an important regulator and mediator of cytokine response to injury. We investigated how NF-κB binding responded to PHx by quantifying the number of genes bound by NF-κB at each time measured post-PHx. The genes bound at each time point included both genes unique to that time point and common among time points. We found that the total number of genes bound by NF-κB during the first 6 h post-PHx was similar at each time point investigated, with 2518 genes bound by NF-κB at baseline (0 h), 2440 genes bound at 1 h post-PHx, and 2396 genes bound at 6 h post-PHx (using an FDR cutoff ≤0.05), although, as the priming phase progressed, the numbers of genes bound by NF-κB decreased. Thus, although NF-κB has been shown to become activated quickly following PHx and maintain its activity until at least the end of the priming phase, the overall number of genes bound by NF-κB during the priming phase of liver regeneration remained similar in our analysis. What changed, however, was the distance from the binding site to the transcription start site (TSS) of the nearest gene (Figure 1). At 0 and 6 h post-PHx, NF-κB binding occurs with two peaks with similar frequency: one upstream of the TSS and one downstream. At 1 h post-PHx, NF-κB binds to both upstream and downstream of the TSS but the downstream binding is clustered closer to the TSS than for 0 and 6 h. Additionally, the upstream and downstream peaks appear higher at 1 h than at 0 or 6 h, indicating that NF-κB binds more genes close to their TSS at 1 h (Figure 1). Transcription factors binding closer to the TSS of a gene have a stronger effect on regulation of gene expression (Cheng and Gerstein, 2012; Cheng et al., 2012). Taken together, our data suggest that at 1 h following PHx NF-κB has a stronger effect on bound genes. This correlates with previous studies showing increased NF-κB activity at 1 h post-PHx (Juskeviciute et al., 2008).


A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes.

Cook DJ, Patra B, Kuttippurathu L, Hoek JB, Vadigepalli R - Front Physiol (2015)

Distance to transcription start site (TSS) at each time measured post-PHx. At 1 h post-PHx, the peak distance to TSS appears to decrease with more NF-κB binding close to the regulated gene both upstream and downstream.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493398&req=5

Figure 1: Distance to transcription start site (TSS) at each time measured post-PHx. At 1 h post-PHx, the peak distance to TSS appears to decrease with more NF-κB binding close to the regulated gene both upstream and downstream.
Mentions: NF-κB is an important regulator and mediator of cytokine response to injury. We investigated how NF-κB binding responded to PHx by quantifying the number of genes bound by NF-κB at each time measured post-PHx. The genes bound at each time point included both genes unique to that time point and common among time points. We found that the total number of genes bound by NF-κB during the first 6 h post-PHx was similar at each time point investigated, with 2518 genes bound by NF-κB at baseline (0 h), 2440 genes bound at 1 h post-PHx, and 2396 genes bound at 6 h post-PHx (using an FDR cutoff ≤0.05), although, as the priming phase progressed, the numbers of genes bound by NF-κB decreased. Thus, although NF-κB has been shown to become activated quickly following PHx and maintain its activity until at least the end of the priming phase, the overall number of genes bound by NF-κB during the priming phase of liver regeneration remained similar in our analysis. What changed, however, was the distance from the binding site to the transcription start site (TSS) of the nearest gene (Figure 1). At 0 and 6 h post-PHx, NF-κB binding occurs with two peaks with similar frequency: one upstream of the TSS and one downstream. At 1 h post-PHx, NF-κB binds to both upstream and downstream of the TSS but the downstream binding is clustered closer to the TSS than for 0 and 6 h. Additionally, the upstream and downstream peaks appear higher at 1 h than at 0 or 6 h, indicating that NF-κB binds more genes close to their TSS at 1 h (Figure 1). Transcription factors binding closer to the TSS of a gene have a stronger effect on regulation of gene expression (Cheng and Gerstein, 2012; Cheng et al., 2012). Taken together, our data suggest that at 1 h following PHx NF-κB has a stronger effect on bound genes. This correlates with previous studies showing increased NF-κB activity at 1 h post-PHx (Juskeviciute et al., 2008).

Bottom Line: We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy.These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns.Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Anatomy and Cell Biology, Daniel Baugh Institute for Functional Genomics/Computational Biology, Thomas Jefferson University Philadelphia, PA, USA ; Department of Chemical and Biomolecular Engineering, University of Delaware Newark, DE, USA.

ABSTRACT
Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-κB) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-κB binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-κB through categorizing NF-κB binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-κB binding by relating the temporal response profile to differential gene expression. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-κB also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-κB regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.

No MeSH data available.


Related in: MedlinePlus