Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles

Hikichi, Takafusa; Matoba, Ryo; Ikeda, Takashi; Watanabe, Akira; Yamamoto, Takuya; Yoshitake, Satoko; Tamura‐Nakano, Miwa; Kimura, Takayuki; Kamon, Masayoshi; Shimura, Mari; Kikuchi, Kôichi; Okuda, Akihiko; Okochi, Hitoshi; Inoue, Takafumi; Suzuki, Atsushi; Masui, Shinji

doi:10.1073/pnas.1220200110

Cited by 40 publications

(63 citation statements)

References 39 publications

(53 reference statements)

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“…The present finding that miR122 is downregulated by GRHL2 might provide an explanation for such mechanisms. Recently, it was demonstrated that key transcription factors defining neural lineage cells, including PAX6 and ETV6, inhibit dedifferentiation induced by OCT3/4 (POU5F1), SOX2, KLF4 and cMYC during reprograming (Hikichi et al, 2013). As we have previously demonstrated (Senga et al, 2012;Tanimizu et al, 2013), GRHL2 is a key transcription factor in inducing the cellular properties of mature cholangiocytes.…”

Section: Discussionmentioning

confidence: 76%

Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells

et al. 2014

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Late fetal and adult livers are reported to contain bipotential liver stem/ progenitor cells (LPCs), which share surface markers, including epithelial cell adhesion molecule (EpCAM), with cholangiocytes and differentiate into both hepatocytes and cholangiocytes. However, recent results do not necessarily support the idea that LPCs contribute significantly to cellular turnover and regeneration by supplying new hepatocytes. Here, we examined the colony-forming capability of EpCAM + cells isolated from mouse livers between E17 and 11 weeks of age. We found that the number of bipotential colonies was greatly reduced between 1 and 6 weeks, indicating that the number of LPCs decreases during postnatal development. Moreover, bipotential colonies derived from adult LPCs contained substantially fewer albumin + cells than those from neonatal LPCs. We further examined the differentiation potential of neonatal and adult LPCs by transplantation and found that neonatal cells differentiated into mature hepatocytes in recipient livers more frequently than adult LPCs. Since we previously reported that the transcription factor grainyhead-like 2 (GRHL2) expressed in EpCAM + cells inhibits hepatocytic differentiation, we examined whether targets of GRHL2 might block hepatocytic differentiation. DNA and microRNA microarrays revealed that miR122, the expression of which correlates with hepatocytic differentiation, was greatly reduced in adult as compared with neonatal EpCAM + cells. Indeed, GRHL2 negatively regulates the promoter/enhancer activity of the Mir122 gene. Our results indicate that neonatal but not adult EpCAM + LPCs have great potential to produce albumin + hepatocytes. GRHL2 suppresses transcription of miR122 and thereby restricts the differentiation potential of adult LPCs.

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Section: Discussionmentioning

confidence: 76%

Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells

et al. 2014

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“…Cellular differentiation, as well as reprogramming, results in global alterations of the transcriptional program and epigenetic modifications such as DNA methylation (18,19). On the other hand, misregulated differentiation can lead to aberrant transdifferentiation and abnormal cellular states, such as cancer (20)(21)(22).In this study our established in vitro circadian clock formation assay clearly shows that the constitutive expression of c-Myc and Dnmt1 −/− disrupted the development of the circadian clock. Global gene expression analysis reveals that 484 genes are identified as candidate factors correlating with emergence of circadian clock oscillation.…”

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confidence: 59%

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confidence: 99%

Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells

Umemura

Koike

Matsumoto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock in mammalian cells is cell-autonomously generated during the cellular differentiation process, but the underlying mechanisms are not understood. Here we show that perturbation of the transcriptional program by constitutive expression of transcription factor c-Myc and DNA methyltransferase 1 (Dnmt1) ablation disrupts the differentiation-coupled emergence of the clock from mouse ESCs. Using these model ESCs, 484 genes are identified by global gene expression analysis as factors correlated with differentiation-coupled circadian clock development. Among them, we find the misregulation of Kpna2 (Importin-α2) during the differentiation of the c-Myc-overexpressed and Dnmt1 −/− ESCs, in which sustained cytoplasmic accumulation of PER proteins is observed. Moreover, constitutive expression of Kpna2 during the differentiation culture of ESCs significantly impairs clock development, and KPNA2 facilitates cytoplasmic localization of PER1/2. These results suggest that the programmed gene expression network regulates the differentiation-coupled circadian clock development in mammalian cells, at least in part via posttranscriptional regulation of clock proteins.T he circadian clock is an intrinsic time-keeping system that regulates essential physiological functions such as sleep/wake cycles, body temperature, and metabolism (1-3). In the mammalian clock system the central pacemaker resides in the suprachiasmatic nucleus of the hypothalamus, coordinating cell-autonomous molecular oscillators throughout the body to perform tissue-specific functions. The molecular oscillator consists of transcriptional/ translational feedback loops of clock genes. Two transcription factors, CLOCK and BMAL1, heterodimerize and transactivate core clock genes such as the Period (Per1, 2, 3), Cryptochrome (Cry1, 2), and Rev-Erbα genes via E-box regulatory elements. PER and CRY proteins, in turn, translocate into the nucleus to suppress CLOCK/BMAL1 activity, leading to cyclic expression of these clock genes (4-9). Furthermore, REV-ERBα negatively regulates Bmal1 transcription via the RORE promoter element, thus driving antiphasic expression patterns of Bmal1 (10, 11).Despite uncovering the emergence of the circadian rhythms that occur during development (12-14), the precise mechanism of circadian clock development in mammalian cells remains unclear. Recently it has been found that pluripotent ES cells (ESCs) do not display discernible circadian molecular oscillations, whereas in vitro-differentiated ESCs displayed robust circadian oscillations of reporter expression (15-17). Moreover, we also have shown that circadian oscillations were abolished when differentiated cells were reprogrammed to regain pluripotency by expression of reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) (15). These results suggested that the emergence of the cell-autonomous circadian oscillator is coupled with cellular differentiation. Cellular differentiation, as well as reprogramming, results in global alterations of the transcriptional program and epi...

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“…Indeed, depletion of the B cell-specifying TF Pax5 or ectopic expression of its antagonist CEB/P-alpha enables the reprogramming of terminally differentiated B cells 18 . Conversely, forced expression of lineage-specific TFs, in combination with OKSM, significantly impairs iPSC formation by sustaining a somatic gene expression program and preventing activation of pluripotency genes 19 . Together, these findings demonstrate that reprogramming TFs have to achieve two key tasks, namely the extinction of the somatic program, which is maintained by counteracting TFs, and the induction of a stable pluripotent state typical of ESCs.…”

Section: Mechanisms Of Induced Pluripotencymentioning

confidence: 99%

Chromatin dynamics during cellular reprogramming

Apostolou

Hochedlinger

2013

Nature

356

333

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Preface Induced pluripotency is a powerful tool to derive patient-specific stem cells. In addition, it provides a unique assay to study the interplay between transcription factors and chromatin structure. Here, we review the latest insights into chromatin dynamics inherent to induced pluripotency. Moreover, we compare and contrast these events with other physiological and pathological processes involving changes in chromatin and cell state, including germ cell maturation and tumorigenesis. We propose that an integrated view of these seemingly diverse processes could provide mechanistic insights into cell fate transitions in general and might lead to novel approaches in regenerative medicine and cancer treatment.

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Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles

Cited by 40 publications

References 39 publications

Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells

Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells

Transcriptional program of Kpna2/Importin-α2 regulates cellular differentiation-coupled circadian clock development in mammalian cells

Chromatin dynamics during cellular reprogramming

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