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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

Pattern-based motif analysis of NF-κB binding sites. Strongly bound sites in each binding pattern were matched to known transcription factor binding sites using the software DME and the TRANSFAC database. Potential co-regulators of NF-κB binding switches were identified for each binding pattern.
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Figure 4: Pattern-based motif analysis of NF-κB binding sites. Strongly bound sites in each binding pattern were matched to known transcription factor binding sites using the software DME and the TRANSFAC database. Potential co-regulators of NF-κB binding switches were identified for each binding pattern.

Mentions: NF-κB binding motif analysis revealed that NF-κB had multiple cofactors that may act to help regulate transcription following PHx (Figure 4, Figure S6). We found several motifs associated with the immediate NF-κB switch in the AP-1 and ATF families. AP-2 in particular may be a cofactor helping to regulate genes within this switch. C/EBP-gamma was also associated with both the binding (black) and unbinding patterns (gray). The binding pattern (black) in the transient response switch was associated with transcription factors related to cellular response to stress (metabolic Oct-1 or heat HSF), immune response (AIRE, HSF) and the cell cycle (MEF-2). Whereas the transient unbinding pattern (gray) was associated with transcription factors related to immediate-early gene expression (AP-2a and ATF6) and those that may relate to transcriptional control of hepatic stellate cell activation (SMAD3 and TAL1). The delayed NF-κB switch was associated with many of these same transcription factors (AP-2, AP-3, ATF, ATF-4, SMAD3, and MEF-2) as well as several additional transcription factors involved in inflammation (IRF-1) and the cell cycle (c-Myc). Constitutive NF-κB binding was associated with similar transcription factors (AP-4, ATF, ATF-3, and MEF-2).


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)

Pattern-based motif analysis of NF-κB binding sites. Strongly bound sites in each binding pattern were matched to known transcription factor binding sites using the software DME and the TRANSFAC database. Potential co-regulators of NF-κB binding switches were identified for each binding pattern.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Pattern-based motif analysis of NF-κB binding sites. Strongly bound sites in each binding pattern were matched to known transcription factor binding sites using the software DME and the TRANSFAC database. Potential co-regulators of NF-κB binding switches were identified for each binding pattern.
Mentions: NF-κB binding motif analysis revealed that NF-κB had multiple cofactors that may act to help regulate transcription following PHx (Figure 4, Figure S6). We found several motifs associated with the immediate NF-κB switch in the AP-1 and ATF families. AP-2 in particular may be a cofactor helping to regulate genes within this switch. C/EBP-gamma was also associated with both the binding (black) and unbinding patterns (gray). The binding pattern (black) in the transient response switch was associated with transcription factors related to cellular response to stress (metabolic Oct-1 or heat HSF), immune response (AIRE, HSF) and the cell cycle (MEF-2). Whereas the transient unbinding pattern (gray) was associated with transcription factors related to immediate-early gene expression (AP-2a and ATF6) and those that may relate to transcriptional control of hepatic stellate cell activation (SMAD3 and TAL1). The delayed NF-κB switch was associated with many of these same transcription factors (AP-2, AP-3, ATF, ATF-4, SMAD3, and MEF-2) as well as several additional transcription factors involved in inflammation (IRF-1) and the cell cycle (c-Myc). Constitutive NF-κB binding was associated with similar transcription factors (AP-4, ATF, ATF-3, and MEF-2).

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