HNF4α Combinatorial Isoform Heterodimers Activate Distinct Gene Targets that Differ from Their Corresponding Homodimers

Ko, Hui Ling; Zhuo, Ziyi; Ren, Ee Chee

doi:10.1016/j.celrep.2019.02.033

Cited by 41 publications

(81 citation statements)

References 47 publications

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“…These two isoform classes differ in both their N and C termini . Therefore, HNF4α expression during spontaneous differentiation of Caco‐2 cells was examined with two different HNF4α antibody clones: clone C‐19, which can recognize isoforms 1, 2, 4, 5, 7, 8, and 9, and clone K9218, which can detect isoforms 1, 2, and 3 . We have observed enhanced expression of HNF4α with both antibodies (Fig.…”

Section: Resultsmentioning

confidence: 81%

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

et al. 2019

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Intestinal epithelial cells are derived from stem cells at the crypts that undergo differentiation into transit‐amplifying cells, which in turn form terminally differentiated enterocytes as these cells reach the villus. Extensive alterations in both transcriptional and translational programs occur during differentiation, which can induce the activation of cellular stress responses such as ER stress‐related unfolded protein response (UPR) and autophagy, particularly in the cells that are already committed to becoming absorptive cells. Using an epithelial cell model of enterocyte differentiation, we report a mechanistic study connecting enterocyte differentiation to UPR and autophagy. We report that differentiated colon epithelial cells showed increased cytosolic Ca2+ levels and activation of all three pathways of UPR: inositol‐requiring enzyme 1 (IRE1), protein kinase RNA‐like ER kinase, and activating transcription factor 6 (ATF6) compared to the undifferentiated cells. Enhanced UPR in the differentiated cells was accompanied by the induction of autophagy as evidenced by increased ratio of light chain 3 II/I, upregulation of Beclin‐1, and downregulation of p62. We show for the first time that mechanistically, the upregulation of hepatocyte nuclear factor 4α (HNF4α) during differentiation led to increased promoter binding and transcriptional upregulation of two major proteins of UPR: X‐box binding protein‐1 and ATF6, implicating HNF4α as a key regulator of UPR response during differentiation. Integrating wet‐lab with in silico analyses, the present study links differentiation to cellular stress responses, and highlights the importance of transcription factor signaling and cross‐talk between the cellular events in the regulation of intestinal cell differentiation.

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Section: Resultsmentioning

confidence: 81%

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

et al. 2019

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“…This has led to contradictory functions being attributed to HNF4α as a consequence of studying different isoforms (Babeu et al, 2018; Chellappa et al, 2016; Vuong et al, 2015). In order to simplify the nomenclature of the isoforms, we now propose to follow the P1 and P2 classification of isoforms, first by sorting the isoforms from the N-termini, and then by the different C-termini as also suggested by (Ko et al, 2019). This leads to four main classes of isoforms (P1a, P1b, P2a, P2b) (Figure 1), and maintains the order of the different C-termini in order to remain consistent with the nomenclature used in most previous studies.…”

Section: Resultsmentioning

confidence: 99%

“…HNF4α was initially considered to be an exclusive homodimer, (Jiang et al, 1995). However, recent evidence demonstrate that HNF4α can also form heterodimers, with distinct gene targets from the corresponding homodimers (Ko et al, 2019), and several tissues and cell lines express more than one isoform (Figure 2, Supplementary Figure 1 and (Ko et al, 2019)). The overexpression of different homodimers and heterodimers appears to regulate differentially a subset of previously reported genes, as well as inflammatory genes, underlining the importance of further studies that will tackle the complete transcriptome regulated by different combinations of HNF4α isoforms.…”

Section: Discussionmentioning

confidence: 99%

Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions

Lambert

Babeu

Simoneau

et al. 2019

Preprint

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“…Twelve isoforms of HNF4a have been identified to date (23), which arise as a result of transcription from two different promoters (P1 and P2) as well as alternative exon splicing. The P1 and P2 promoters are activated in a tissue-specific manner, and P1 and P2 isoforms have distinct roles in tumorigenesis (24,25).…”

Section: Hnf4a Deletion Accelerates Tumorigenesis In a Mouse Model Ofmentioning

confidence: 99%

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

Camolotto

Belova

Torre-Healy

et al. 2019

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: Classical and Basal-like. The Classical subtype is characterized by a more favorable prognosis and better response to chemotherapy than the Basal-like subtype. The Classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor HNF4a. Using in vitro and in vivo PDAC models, we show that HNF4a restrains tumor growth and drives tumor cells toward an epithelial identity.Gene expression analysis from murine models and human tumors shows that HNF4a activates expression of genes associated with the Classical subtype. Although HNF4a loss is not sufficient for complete conversion to the Basal-like subtype gene expression profile, HNF4a directly represses SIX4 and SIX1, mesodermal lineage specifiers expressed in the Basal-like subtype.Finally, HNF4a-negative PDAC cells rely on expression of SIX4 and SIX1 for proliferation in vitro and in vivo. Overall, our data show that HNF4a regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the Classical gene expression program and repression of SIX4 and SIX1, which may represent novel dependencies of the Basal-like subtype.

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HNF4α Combinatorial Isoform Heterodimers Activate Distinct Gene Targets that Differ from Their Corresponding Homodimers

Cited by 41 publications

References 47 publications

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

Enhanced expression of HNF4α during intestinal epithelial differentiation is involved in the activation of ER stress

Human Hepatocyte Nuclear Factor 4-α encodes isoforms with distinct transcriptional functions

Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4

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