A Synthetic Small Molecule for Targeted Transcriptional Activation of Germ Cell Genes in a Human Somatic Cell

Han, Le; Pandian, Ganesh N.; Syed, Junetha; Sato, Shinsuke; Chandran, Anandhakumar; Taniguchi, Jun; Saha, Abhijit; Bando, Toshikazu; Nagase, Hiroki; Sugiyama, Hiroshi

doi:10.1002/ange.201306766

Cited by 21 publications

(12 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a SAHA‐PIP called K got categorized as the first‐ever small molecule capable of enforcing transcriptional activation of meiosis‐regulating germ cell genes in a human somatic cell [75]. This result substantiates the remarkable ability of SAHA‐PIP to activate silent genes because these germ cell specific meiotic markers do not normally occur in a somatic cell.…”

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 78%

“…(B) SAHA‐PIP ` δ` triggers the core pluripotency gene network in mouse embryonic fibroblasts through site‐specific epigenetic activation. In human dermal fibroblasts [74], (C) SAHA‐PIP K and (D) SAHA‐PIP A activates gene regulatory network associated with and germ cell and pancreas function such as glucose metabolism, respectively [12,75].…”

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 99%

“…Moreover, transcriptome analysis suggested that effect of A is associated with pancreas‐related function such as glucose metabolism and diabetes [10] (Figure 5D). Chromatin immune precipitation studies have revealed that SAHA‐PIP can induce site‐specific chromatin modification to activate the typically ‘silent genes’ in human somatic cells [75]. Because of the tunable potential, SAHA‐PIP could be developed as a novel tool to achieve precisely reprogrammed pluripotent stem cell and/or insulin producing β cell.…”

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 99%

See 2 more Smart Citations

Cellular reprogramming for pancreatic β‐cell regeneration: clinical potential of small molecule control

Pandian

Taniguchi

Sugiyama

2014

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

Recent scientific breakthroughs in stem cell biology suggest that a sustainable treatment approach to cure diabetes mellitus (DM) can be achieved in the near future. However, the transplantation complexities and the difficulty in obtaining the stem cells from adult cells of pancreas, liver, bone morrow and other cells is a major concern. The epoch‐making strategy of transcription‐factor based cellular reprogramming suggest that these barriers could be overcome, and it is possible to reprogram any cells into functional β cells. Contemporary biological and analytical techniques help us to predict the key transcription factors needed for β‐cell regeneration. These β cell‐specific transcription factors could be modulated with diverse reprogramming protocols. Among cellular reprogramming strategies, small molecule approach gets proclaimed to have better clinical prospects because it does not involve genetic manipulation. Several small molecules targeting certain epigenetic enzymes and/or signaling pathways have been successful in helping to induce pancreatic β‐cell specification. Recently, a synthetic DNA‐based small molecule triggered targeted transcriptional activation of pancreas‐related genes to suggest the possibility of achieving desired cellular phenotype in a precise mode. Here, we give a brief overview of treating DM by regenerating pancreatic β‐cells from various cell sources. Through a comprehensive overview of the available transcription factors, small molecules and reprogramming strategies available for pancreatic β‐cell regeneration, this review compiles the current progress made towards the generation of clinically relevant insulin‐producing β‐cells.

show abstract

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 78%

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 99%

Section: Cellular Reprogramming and Beta Cell Regenerationmentioning

confidence: 99%

See 1 more Smart Citation

Cellular reprogramming for pancreatic β‐cell regeneration: clinical potential of small molecule control

Pandian

Taniguchi

Sugiyama

2014

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…By conjugating PIP with a HDAC inhibitor SAHA, our group previously developed a class of designer molecule called SAHA-PIP for sequence-selective histone acetylation. 8 SAHA-PIPs with different sequence-specificity activated silenced genes including pluripotency genes, 9,10 germ cell-associated genes, 11 retinal genes, 12 neural genes, 13 and key therapeutically important genes 14 in human dermal fibroblasts. Despite the proclaimed potential of SAHA-PIPs as epigenetic drugs, the level of gene activation was still inconsistent.…”

Section: ■ Introductionmentioning

confidence: 99%

Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones

et al. 2018

Self Cite

View full text Add to dashboard Cite

While the central role of locus-specific acetylation of histone proteins in eukaryotic gene expression is well established, the availability of designer tools to regulate acetylation at particular nucleosome sites remains limited. Here, we develop a unique strategy to introduce acetylation by constructing a bifunctional molecule designated Bi-PIP. Bi-PIP has a P300/CBP-selective bromodomain inhibitor (Bi) as a P300/CBP recruiter and a pyrrole-imidazole polyamide (PIP) as a sequence-selective DNA binder. Biochemical assays verified that Bi-PIPs recruit P300 to the nucleosomes having their target DNA sequences and extensively accelerate acetylation. Bi-PIPs also activated transcription of genes that have corresponding cognate DNA sequences inside living cells. Our results demonstrate that Bi-PIPs could act as a synthetic programmable histone code of acetylation, which emulates the bromodomain-mediated natural propagation system of histone acetylation to activate gene expression in a sequence-selective manner.

show abstract

“…Dozens of epigenetic agents, such as histone deacetylase (HDAC) inhibitors (SAHA and TSA), histone acetyltransferase ( HAT) activators (CTB and CTPB) and HAT inhibitors (C646 and anacardic acid), have been approved or are in preclinical development and show promising therapeutic efficacy [2][3][4]. In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators have recently gained prominence as an emerging class of versatile synthetic dual-function ligands that achieve regulatory control over multi-gene networks (Figure 1) [5,6]. Our lab has focused on sequence-specific epigenetic regulators that involve conjugation with DNA-binding domains (DBDs) and pyrrole-imidazole polyamides (PIPs) [7].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

Taniguchi

Wei

et al. 2017

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC of 1.8-2.6 μM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics.

show abstract

A Synthetic Small Molecule for Targeted Transcriptional Activation of Germ Cell Genes in a Human Somatic Cell

Cited by 21 publications

References 29 publications

Cellular reprogramming for pancreatic β‐cell regeneration: clinical potential of small molecule control

Cellular reprogramming for pancreatic β‐cell regeneration: clinical potential of small molecule control

Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

Contact Info

Product

Resources

About