Enhanced expression of HNF4 alpha during intestinal epithelial differentiation is involved in the activation of ER stress

Tuncer, Sinem
Sade-Memişoğlu, Aslı
Keşküş, Ayşe Gökçe
Sheraj, Ilir
Güner, Güneş
Akyol, Aytekin
Banerjee, Sreeparna
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 4 alpha (HNF4 alpha) during differentiation led to increased promoter binding and transcriptional upregulation of two major proteins of UPR: X-box binding protein-1 and ATF6, implicating HNF4 alpha 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.
FEBS Journal


Characterization and identification of human mesenchymal stem cells at molecular level
Aksoy, Ceren; Severcan, Feride; Çetinkaya, Duygu Uçkan; Department of Biotechnology (2012)
Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FT...
Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG
Yildiz, Soner; Alpdundar, Esin; Gungor, Bilgi; Kahraman, Tamer; Bayyurt, Banu; GÜRSEL, İHSAN; Gürsel, Mayda (2015-04-01)
Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrat...
Rapid differentiation of MSC into adipocytes and osteocytes is facilitated by Toll-Like receptor engagement
Tas, Ibrahim; Tokcaer-Keskin, Zeynep; Ayhan, Fatma; Gürsel, Mayda; Akcali, Kamil (2010-04-01)
Mesenchymal stem cells are multipotent progenitor cells capable of differentiating into several lineages including adipocytes, and osteocytes. While they are regarded as non-immunogenic, accumulating evidence suggests that MSC expresses several TLRs. We checked the contribution of TLR ligands to MSC differentiation. Rat bone marrow derived MSC surface marker and TLR transcript levels were checked by FACS and RT-PCR respectively. MSCs were CD29hi, CD71dim, CD90hi, and negative for CD45 & CD34. They expressed...
Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib
Kahraman, Deniz Cansen; Kahraman, Tamer; Atalay, Rengül (2018-07-01)
Liver cancer stem cells (LCSCs) are derived from damaged and transformed hepatic progenitor cells (HPCs) during precancerous cirrhosis stage. Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are significantly deregulated in liver cancer. The activation of PI3K/AKT/mTOR pathway in LCSC population is one of the reasons for acquired resistance to sorafenib in advanced hepatocellular carcinoma (HCC) patients. Therefore, identifying novel inhibitors targeting this pathway acting on LCSCs is highly essential. We...
Evaluating Oxygen Tensions Related to Bone Marrow and Matrix for MSC Differentiation in 2D and 3D Biomimetic Lamellar Scaffolds
Sayin, Esen; Baran, Erkan Turker; Elsheikh, Ahmed; Mudera, Vivek; Cheema, Umber; Hasırcı, Vasıf Nejat (2021-04-01)
The physiological O-2 microenvironment of mesenchymal stem cells (MSCs) and osteoblasts and the dimensionality of a substrate are known to be important in regulating cell phenotype and function. By providing the physiologically normoxic environments of bone marrow (5%) and matrix (12%), we assessed their potential to maintain stemness, induce osteogenic differentiation, and enhance the material properties in the micropatterned collagen/silk fibroin scaffolds that were produced in 2D or 3D. Expression of ost...
Citation Formats
S. Tuncer et al., “Enhanced expression of HNF4 alpha during intestinal epithelial differentiation is involved in the activation of ER stress,” FEBS Journal, pp. 2504–2523, 2019, Accessed: 00, 2020. [Online]. Available: https://doi.org/10.1111/febs.15152.