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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

Switching mechanisms of NF-κB binding post-PHx. (A) NF-κB immediate response switch. (B) NF-κB transient response switch. (C) NF-κB delayed switch. (D) NF-κB constitutive binding. NF-κB was constitutively bound to genes responsible for cell cycle, cellular response to stress, and the JAK-STAT pathway. The regulation of these genes by NF-κB may be essential for tissue function.
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Figure 3: Switching mechanisms of NF-κB binding post-PHx. (A) NF-κB immediate response switch. (B) NF-κB transient response switch. (C) NF-κB delayed switch. (D) NF-κB constitutive binding. NF-κB was constitutively bound to genes responsible for cell cycle, cellular response to stress, and the JAK-STAT pathway. The regulation of these genes by NF-κB may be essential for tissue function.

Mentions: In light of the role of NF-κB in dynamically regulating tissue function post-PHx, we next investigated how NF-κB switches regulated gene expression. We first used the NF-κB switches to organize genes into binding patterns as before (Figure 3, left panel). We then identified gene expression levels of genes bound by NF-κB using a previously published RNA-seq gene expression data set of rat liver regeneration at 0, 4, and 12 h post-PHx (Figure 3, center panel; Table 1). Genes were identified as differentially expressed with a fold-change value ≥2 (see Material and Methods for rationale). Differentially expressed genes corresponding to each NF-κB switch were then analyzed to identify functional clusters of genes using the DAVID software (Figure 3, right panel) (Huang et al., 2009). For constitutive NF-κB binding, all NF-κB bound genes were analyzed rather than only differentially expressed genes. This association of NF-κB binding with subsequent gene expression was somewhat tenuous because of the low sampling frequency and non-identical time points used between studies; however, this approach focused our analysis to NF-κB binding that appears to have a dynamic functional role in gene expression.


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)

Switching mechanisms of NF-κB binding post-PHx. (A) NF-κB immediate response switch. (B) NF-κB transient response switch. (C) NF-κB delayed switch. (D) NF-κB constitutive binding. NF-κB was constitutively bound to genes responsible for cell cycle, cellular response to stress, and the JAK-STAT pathway. The regulation of these genes by NF-κB may be essential for tissue function.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Switching mechanisms of NF-κB binding post-PHx. (A) NF-κB immediate response switch. (B) NF-κB transient response switch. (C) NF-κB delayed switch. (D) NF-κB constitutive binding. NF-κB was constitutively bound to genes responsible for cell cycle, cellular response to stress, and the JAK-STAT pathway. The regulation of these genes by NF-κB may be essential for tissue function.
Mentions: In light of the role of NF-κB in dynamically regulating tissue function post-PHx, we next investigated how NF-κB switches regulated gene expression. We first used the NF-κB switches to organize genes into binding patterns as before (Figure 3, left panel). We then identified gene expression levels of genes bound by NF-κB using a previously published RNA-seq gene expression data set of rat liver regeneration at 0, 4, and 12 h post-PHx (Figure 3, center panel; Table 1). Genes were identified as differentially expressed with a fold-change value ≥2 (see Material and Methods for rationale). Differentially expressed genes corresponding to each NF-κB switch were then analyzed to identify functional clusters of genes using the DAVID software (Figure 3, right panel) (Huang et al., 2009). For constitutive NF-κB binding, all NF-κB bound genes were analyzed rather than only differentially expressed genes. This association of NF-κB binding with subsequent gene expression was somewhat tenuous because of the low sampling frequency and non-identical time points used between studies; however, this approach focused our analysis to NF-κB binding that appears to have a dynamic functional role in gene expression.

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