Limits...
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

Co-ordinated activation of AP-1 and ATF family transcription factors during liver regeneration. Our motif analysis suggested that AP-1 binding coincided with NF-κB binding to co-regulate expression of genes during the priming phase of liver regeneration. The AP-1 family of transcription factors was found to be strongly activated by 1 h post-PHx in rats. This activation was maintained throughout the priming phase for all transcription factors except FOSB and JUNB. FOSB activity decreased following PHx, which JUNB activity transiently increased before returning to baseline levels. *p-value < 0.05, **p-value < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493398&req=5

Figure 5: Co-ordinated activation of AP-1 and ATF family transcription factors during liver regeneration. Our motif analysis suggested that AP-1 binding coincided with NF-κB binding to co-regulate expression of genes during the priming phase of liver regeneration. The AP-1 family of transcription factors was found to be strongly activated by 1 h post-PHx in rats. This activation was maintained throughout the priming phase for all transcription factors except FOSB and JUNB. FOSB activity decreased following PHx, which JUNB activity transiently increased before returning to baseline levels. *p-value < 0.05, **p-value < 0.01.

Mentions: Our motif analysis found several motifs enriched in NF-κB binding sites belonging to the AP-1 and ATF transcription factor families. We therefore investigated the dynamics of AP-1 and ATF transcription factor family activities during the priming phase post-PHx. We found that the AP-1 family of transcription factors was strongly activated by 1 h post-PHx in rats and remained activated over the course of the priming phase (Figure 5A). This behavior was true for AP-1 family all transcription factors measured except FOSB and JUNB. FOSB activity decreased following PHx, while JUNB activity showed little change (Figure 5B). ATF family transcription factor activities were also increased above baseline throughout the priming phase (Figure 5C). These results coupled with the potential co-regulatory binding sites identified with NF-κB indicate that, as expected, AP-1 and ATF family transcription factors coordinate with NF-κB in regulating the priming for liver regeneration.


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)

Co-ordinated activation of AP-1 and ATF family transcription factors during liver regeneration. Our motif analysis suggested that AP-1 binding coincided with NF-κB binding to co-regulate expression of genes during the priming phase of liver regeneration. The AP-1 family of transcription factors was found to be strongly activated by 1 h post-PHx in rats. This activation was maintained throughout the priming phase for all transcription factors except FOSB and JUNB. FOSB activity decreased following PHx, which JUNB activity transiently increased before returning to baseline levels. *p-value < 0.05, **p-value < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Co-ordinated activation of AP-1 and ATF family transcription factors during liver regeneration. Our motif analysis suggested that AP-1 binding coincided with NF-κB binding to co-regulate expression of genes during the priming phase of liver regeneration. The AP-1 family of transcription factors was found to be strongly activated by 1 h post-PHx in rats. This activation was maintained throughout the priming phase for all transcription factors except FOSB and JUNB. FOSB activity decreased following PHx, which JUNB activity transiently increased before returning to baseline levels. *p-value < 0.05, **p-value < 0.01.
Mentions: Our motif analysis found several motifs enriched in NF-κB binding sites belonging to the AP-1 and ATF transcription factor families. We therefore investigated the dynamics of AP-1 and ATF transcription factor family activities during the priming phase post-PHx. We found that the AP-1 family of transcription factors was strongly activated by 1 h post-PHx in rats and remained activated over the course of the priming phase (Figure 5A). This behavior was true for AP-1 family all transcription factors measured except FOSB and JUNB. FOSB activity decreased following PHx, while JUNB activity showed little change (Figure 5B). ATF family transcription factor activities were also increased above baseline throughout the priming phase (Figure 5C). These results coupled with the potential co-regulatory binding sites identified with NF-κB indicate that, as expected, AP-1 and ATF family transcription factors coordinate with NF-κB in regulating the priming for liver regeneration.

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