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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 patterns with associated pathways found using DAVID. (A) Immediate binding and unbinding (B) Transient Binding and unbinding (C) Delayed Binding and Unbinding (D) Constitutive Binding. Our analysis revealed that NF-κB binds to many genes involved in sensory perception of smell at baseline. Following PHx, however, these targets become unbound as NF-κB instead targets pathways previously related to be critical to liver regeneration. It is possible that genes involved in sensory perception of smell serve as a sink for NF-κB binding so that transient pulses to NF-κB binding do not start cascades of inflammation.
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Figure 2: NF-κB binding patterns with associated pathways found using DAVID. (A) Immediate binding and unbinding (B) Transient Binding and unbinding (C) Delayed Binding and Unbinding (D) Constitutive Binding. Our analysis revealed that NF-κB binds to many genes involved in sensory perception of smell at baseline. Following PHx, however, these targets become unbound as NF-κB instead targets pathways previously related to be critical to liver regeneration. It is possible that genes involved in sensory perception of smell serve as a sink for NF-κB binding so that transient pulses to NF-κB binding do not start cascades of inflammation.

Mentions: Activation of pro-inflammatory cytokines during the priming phase is a dynamic process involving multiple regulatory feedbacks. Therefore, we used a dynamic pattern-based strategy to analyze the binding of NF-κB to target genes following PHx. We first discretized NF-κB binding by identifying genes as bound (1) or unbound (0) at each time point post-PHx. To be identified as bound, NF-κB binding had to be seen in 2 out of 3 biological replicates at a time point (FDR ≤ 0.05). Because discretized NF-κB binding has 2 distinct states, we were then able to organize NF-κB binding into 7 dynamic binding patterns (Figure 2). Each pattern is described by both a binary string (i.e., 011) and its digital representation. Therefore, the binding pattern unbound by NF-κB at 0 and 1 h but bound at 6 h post-PHx (binary string 001) becomes pattern 1, the binary string 010 (0 h unbound, 1 h bound, 6 h unbound) becomes pattern 2, and so on until binary string 111 becomes pattern 7 (Table 1).


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 patterns with associated pathways found using DAVID. (A) Immediate binding and unbinding (B) Transient Binding and unbinding (C) Delayed Binding and Unbinding (D) Constitutive Binding. Our analysis revealed that NF-κB binds to many genes involved in sensory perception of smell at baseline. Following PHx, however, these targets become unbound as NF-κB instead targets pathways previously related to be critical to liver regeneration. It is possible that genes involved in sensory perception of smell serve as a sink for NF-κB binding so that transient pulses to NF-κB binding do not start cascades of inflammation.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: NF-κB binding patterns with associated pathways found using DAVID. (A) Immediate binding and unbinding (B) Transient Binding and unbinding (C) Delayed Binding and Unbinding (D) Constitutive Binding. Our analysis revealed that NF-κB binds to many genes involved in sensory perception of smell at baseline. Following PHx, however, these targets become unbound as NF-κB instead targets pathways previously related to be critical to liver regeneration. It is possible that genes involved in sensory perception of smell serve as a sink for NF-κB binding so that transient pulses to NF-κB binding do not start cascades of inflammation.
Mentions: Activation of pro-inflammatory cytokines during the priming phase is a dynamic process involving multiple regulatory feedbacks. Therefore, we used a dynamic pattern-based strategy to analyze the binding of NF-κB to target genes following PHx. We first discretized NF-κB binding by identifying genes as bound (1) or unbound (0) at each time point post-PHx. To be identified as bound, NF-κB binding had to be seen in 2 out of 3 biological replicates at a time point (FDR ≤ 0.05). Because discretized NF-κB binding has 2 distinct states, we were then able to organize NF-κB binding into 7 dynamic binding patterns (Figure 2). Each pattern is described by both a binary string (i.e., 011) and its digital representation. Therefore, the binding pattern unbound by NF-κB at 0 and 1 h but bound at 6 h post-PHx (binary string 001) becomes pattern 1, the binary string 010 (0 h unbound, 1 h bound, 6 h unbound) becomes pattern 2, and so on until binary string 111 becomes pattern 7 (Table 1).

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