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

Abstract

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.

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

“…Hepatocyte nuclear factor 4 alpha (HNF4α) is expressed in intestinal villi (Stegmann et al, 2006) and has been identified as a transcription factor that regulates the expression of genes during intestinal cellular differentiation during endoderm development (Yao et al, 2016). It was recently discovered that HNF4α is involved in the activation of ER stress during intestinal epithelial differentiation (Tunçer et al, 2019), demonstrated by the upregulation of XBP1 and ATF6 (two ER stress mediators) downstream of HNFα activity. This study is important because it ties together the importance of ER stress in maintaining proper ISC proliferation and differentiation (Heijmans et al, 2013) with the fact that HNF4α is expressed in the intestinal villi (Stegmann et al, 2006), which suggests that these two signaling pathways are essential for ISC fate and fitness.…”

Single-cell profiling of the pig cecum at various developmental stages

“…At a tau value threshold of >0.85, we identified 140 TFs displaying cell-type-specific expression ( Figure 1C ), including BCL11A and PAX5 in B cells, FOXP3 and LEF1 in T cells, JDP2 , PRNP , and SOX10 in enteric glial cells, CDX2 , EHF , and HNF4A in epithelial cells, and SOX17 in VECs. Among the identified TFs, many have been implicated in corresponding cell types in other species, e.g., HNF4A ( Boyd et al, 2009 ; Tunçer et al, 2020 ), SOX17 ( Yao et al, 2019 ), and PAX5 ( Cobaleda et al, 2007 ; Medvedovic et al, 2011 ) are essential for intestinal epithelial cell, VECs, and B cell differentiation, respectively. Furthermore, several TFs displayed age-dependent expression patterns (Supplementary Figure S2A).…”

Physical Education Sports Activities in Turkish Ocak’s in the First Years of the Republic (1923-1931)

“…53 Altay kulübünün düzenlediği voleybol, atletizm, bisiklet yarışmalarında dereceye giren sporculara İzmir Türk Ocağında hediye ve ödülleri verilmiştir. 54 Ödemiş Türk Ocağı'nda spor faaliyetleri 1923 yılında kurulan Altınova Güç Yurdu Spor Kulübünün kurulmasıyla başlamıştır. 1928 yılında Küçük Menderes, 55 1930 yılında Yıldırım Spor Ödemiş Türk Ocağı himayesinde faaliyetlerini sürdüren diğer gençlik kulüpleri oldular.…”

“…107 Turgutlu'da da belediye Kasaba Türk Ocağı'na, 13.000 metrekarelik bir spor sahası bağışlamış, bunun dışında 800 lira da para yardımında bulunmuştur. 108 Kasaba (Turgutlu) Türk Ocağı spor sahasının yapılması için müsamere gibi gelir getirici etkinliklerde düzenlemiştir. 109 Nazilli Türk Ocağı 1926 yılında binasına bilardo masası getirerek, bir bilardo salonu oluşturmuş, bilardo oyunu için malzeme siparişi vermiştir.…”