Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration

Jingmin Shu, Betsy T. Kren, Zhilian Xia, Phillip Y P Wong, Lihua Li, Eric A. Hanse, Michael X. Min, Bingshan Li, Jeffrey H. Albrecht, Yan Zeng, Subbaya Subramanian, Clifford J. Steer

Research output: Contribution to journalReview article

53 Citations (Scopus)

Abstract

The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70% partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post-PH ~40% of the miRNAs tested were up-regulated. Conversely, at 24 hours post-PH, ~70% of miRNAs were down-regulated. Furthermore, we established that the genomewide down-regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen, Dgcr8, Dicer, Tarbp2, and Prkra, associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above-mentioned genes were examined and found to be up-regulated at 3 hours post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early phase after PH was involved in the priming and commitment to liver regeneration, whereas the subsequent genomewide down-regulation of miRNAs was required for efficient recovery of liver cell mass. Conclusion: Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.

Original languageEnglish (US)
Pages (from-to)609-619
Number of pages11
JournalHepatology
Volume54
Issue number2
DOIs
StatePublished - Aug 1 2011

Fingerprint

Liver Regeneration
MicroRNAs
Down-Regulation
Hepatectomy
Regulator Genes
Genes
Liver

Cite this

Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration. / Shu, Jingmin; Kren, Betsy T.; Xia, Zhilian; Wong, Phillip Y P; Li, Lihua; Hanse, Eric A.; Min, Michael X.; Li, Bingshan; Albrecht, Jeffrey H.; Zeng, Yan; Subramanian, Subbaya; Steer, Clifford J.

In: Hepatology, Vol. 54, No. 2, 01.08.2011, p. 609-619.

Research output: Contribution to journalReview article

Shu, Jingmin ; Kren, Betsy T. ; Xia, Zhilian ; Wong, Phillip Y P ; Li, Lihua ; Hanse, Eric A. ; Min, Michael X. ; Li, Bingshan ; Albrecht, Jeffrey H. ; Zeng, Yan ; Subramanian, Subbaya ; Steer, Clifford J. / Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration. In: Hepatology. 2011 ; Vol. 54, No. 2. pp. 609-619.
@article{05dee8fd7894405aa4bc66c7487eec53,
title = "Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration",
abstract = "The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70{\%} partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post-PH ~40{\%} of the miRNAs tested were up-regulated. Conversely, at 24 hours post-PH, ~70{\%} of miRNAs were down-regulated. Furthermore, we established that the genomewide down-regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen, Dgcr8, Dicer, Tarbp2, and Prkra, associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above-mentioned genes were examined and found to be up-regulated at 3 hours post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early phase after PH was involved in the priming and commitment to liver regeneration, whereas the subsequent genomewide down-regulation of miRNAs was required for efficient recovery of liver cell mass. Conclusion: Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.",
author = "Jingmin Shu and Kren, {Betsy T.} and Zhilian Xia and Wong, {Phillip Y P} and Lihua Li and Hanse, {Eric A.} and Min, {Michael X.} and Bingshan Li and Albrecht, {Jeffrey H.} and Yan Zeng and Subbaya Subramanian and Steer, {Clifford J.}",
year = "2011",
month = "8",
day = "1",
doi = "10.1002/hep.24421",
language = "English (US)",
volume = "54",
pages = "609--619",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "2",

}

TY - JOUR

T1 - Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration

AU - Shu, Jingmin

AU - Kren, Betsy T.

AU - Xia, Zhilian

AU - Wong, Phillip Y P

AU - Li, Lihua

AU - Hanse, Eric A.

AU - Min, Michael X.

AU - Li, Bingshan

AU - Albrecht, Jeffrey H.

AU - Zeng, Yan

AU - Subramanian, Subbaya

AU - Steer, Clifford J.

PY - 2011/8/1

Y1 - 2011/8/1

N2 - The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70% partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post-PH ~40% of the miRNAs tested were up-regulated. Conversely, at 24 hours post-PH, ~70% of miRNAs were down-regulated. Furthermore, we established that the genomewide down-regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen, Dgcr8, Dicer, Tarbp2, and Prkra, associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above-mentioned genes were examined and found to be up-regulated at 3 hours post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early phase after PH was involved in the priming and commitment to liver regeneration, whereas the subsequent genomewide down-regulation of miRNAs was required for efficient recovery of liver cell mass. Conclusion: Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.

AB - The liver is one of the few organs that have the capacity to regenerate in response to injury. We carried out genomewide microRNA (miRNA) microarray studies during liver regeneration in rats after 70% partial hepatectomy (PH) at early and mid time points to more thoroughly understand their role. At 3, 12, and 18 hours post-PH ~40% of the miRNAs tested were up-regulated. Conversely, at 24 hours post-PH, ~70% of miRNAs were down-regulated. Furthermore, we established that the genomewide down-regulation of miRNA expression at 24 hours was also correlated with decreased expression of genes, such as Rnasen, Dgcr8, Dicer, Tarbp2, and Prkra, associated with miRNA biogenesis. To determine whether a potential negative feedback loop between miRNAs and their regulatory genes exists, 11 candidate miRNAs predicted to target the above-mentioned genes were examined and found to be up-regulated at 3 hours post-PH. Using reporter and functional assays, we determined that expression of these miRNA-processing genes could be regulated by a subset of miRNAs and that some miRNAs could target multiple miRNA biogenesis genes simultaneously. We also demonstrated that overexpression of these miRNAs inhibited cell proliferation and modulated cell cycle in both Huh-7 human hepatoma cells and primary rat hepatocytes. From these observations, we postulated that selective up-regulation of miRNAs in the early phase after PH was involved in the priming and commitment to liver regeneration, whereas the subsequent genomewide down-regulation of miRNAs was required for efficient recovery of liver cell mass. Conclusion: Our data suggest that miRNA changes are regulated by negative feedback loops between miRNAs and their regulatory genes that may play an important role in the steady-state regulation of liver regeneration.

UR - http://www.scopus.com/inward/record.url?scp=79960743857&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960743857&partnerID=8YFLogxK

U2 - 10.1002/hep.24421

DO - 10.1002/hep.24421

M3 - Review article

VL - 54

SP - 609

EP - 619

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 2

ER -