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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

NF-κB binding for the top 20 differentially expressed genes clustered according to NF-κB binding pattern. (A) NF-κB binding at baseline, (B) NF-κB binding at 1 h post-PHx, (C) NF-κB binding at 6 h post-PHx. Black, Bound; Gray, Unbound.
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Figure 7: NF-κB binding for the top 20 differentially expressed genes clustered according to NF-κB binding pattern. (A) NF-κB binding at baseline, (B) NF-κB binding at 1 h post-PHx, (C) NF-κB binding at 6 h post-PHx. Black, Bound; Gray, Unbound.

Mentions: Our results indicate that the acute challenge of a partial hepatectomy causes NF-κB binding in the liver to operate as a dynamic switch regulating tissue function. The immediate, transient, and delayed NF-κB signaling profiles appear to serve different purposes in driving regeneration. Early post-PHx, NF-κB binding transitioned from governing many functions to governing mainly those functions necessary to set hepatocytes up for entry into the cell cycle. These functions were maintained throughout the priming phase. Transiently post-PHx, NF-κB binding transitioned away from binding genes involved in maintaining tissue function and toward binding genes involved in apoptosis, circadian rhythm, and hepatic stellate cell activation. The transient switch may therefore be involved in synchronizing healthy cells for entry into the cell cycle while inducing damaged cells to commit apoptosis. The transient switch may also ensure proper timing of hepatic stellate cell activation following PHx. As the priming phase ended, NF-κB began to regulate many genes setting up hepatocytes to enter the cell cycle. This switch may indicate a role for NF-κB contributing to hepatocyte entry into the cell cycle as regeneration progresses past the priming phase. Additionally, several genes involving mitochondrial function that are bound and unbound in this switch (including Atp5d, NDUFA10, ACSL5, and mfn1) may be important to govern the fraction of metabolic demand delegated to regeneration and that delegated to maintenance of tissue function as hepatocytes enter the cell cycle (Shestopaloff, 2014). The binding patterns of differentially expressed genes with the highest expression (top 20 genes) show dynamic regulation by NF-κB throughout the priming phase (Figure 7).


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)

NF-κB binding for the top 20 differentially expressed genes clustered according to NF-κB binding pattern. (A) NF-κB binding at baseline, (B) NF-κB binding at 1 h post-PHx, (C) NF-κB binding at 6 h post-PHx. Black, Bound; Gray, Unbound.
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Related In: Results  -  Collection

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

Figure 7: NF-κB binding for the top 20 differentially expressed genes clustered according to NF-κB binding pattern. (A) NF-κB binding at baseline, (B) NF-κB binding at 1 h post-PHx, (C) NF-κB binding at 6 h post-PHx. Black, Bound; Gray, Unbound.
Mentions: Our results indicate that the acute challenge of a partial hepatectomy causes NF-κB binding in the liver to operate as a dynamic switch regulating tissue function. The immediate, transient, and delayed NF-κB signaling profiles appear to serve different purposes in driving regeneration. Early post-PHx, NF-κB binding transitioned from governing many functions to governing mainly those functions necessary to set hepatocytes up for entry into the cell cycle. These functions were maintained throughout the priming phase. Transiently post-PHx, NF-κB binding transitioned away from binding genes involved in maintaining tissue function and toward binding genes involved in apoptosis, circadian rhythm, and hepatic stellate cell activation. The transient switch may therefore be involved in synchronizing healthy cells for entry into the cell cycle while inducing damaged cells to commit apoptosis. The transient switch may also ensure proper timing of hepatic stellate cell activation following PHx. As the priming phase ended, NF-κB began to regulate many genes setting up hepatocytes to enter the cell cycle. This switch may indicate a role for NF-κB contributing to hepatocyte entry into the cell cycle as regeneration progresses past the priming phase. Additionally, several genes involving mitochondrial function that are bound and unbound in this switch (including Atp5d, NDUFA10, ACSL5, and mfn1) may be important to govern the fraction of metabolic demand delegated to regeneration and that delegated to maintenance of tissue function as hepatocytes enter the cell cycle (Shestopaloff, 2014). The binding patterns of differentially expressed genes with the highest expression (top 20 genes) show dynamic regulation by NF-κB throughout the priming phase (Figure 7).

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