Distinct DNA-based epigenetic switches trigger transcriptional activation of silent genes in human dermal fibroblasts.
The influential role of the epigenome in orchestrating genome-wide transcriptional activation instigates the demand for the artificial genetic switches with distinct DNA sequence recognition. Recently, we developed a novel class of epigenetically active small molecules called SAHA-PIPs by conjugating selective DNA binding pyrrole-imidazole polyamides (PIPs) with the histone deacetylase inhibitor SAHA. Screening studies revealed that certain SAHA-PIPs trigger targeted transcriptional activation of pluripotency and germ cell genes in mouse and human fibroblasts, respectively. Through microarray studies and functional analysis, here we demonstrate for the first time the remarkable ability of thirty-two different SAHA-PIPs to trigger the transcriptional activation of exclusive clusters of genes and noncoding RNAs. QRT-PCR validated the microarray data, and some SAHA-PIPs activated therapeutically significant genes like KSR2. Based on the aforementioned results, we propose the potential use of SAHA-PIPs as reagents capable of targeted transcriptional activation.
1] Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8502, Japan [2].
Ganesh N
GN
Pandian
1] Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan [2].
Junichi
J
Taniguchi
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Syed
S
Junetha
Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8502, Japan.
Shinsuke
S
Sato
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Le
L
Han
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Abhijit
A
Saha
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Chandran
C
AnandhaKumar
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Toshikazu
T
Bando
1] Division of Cancer Genetics, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo 173-8610, Japan [2] Division of Cancer Genetics, Chiba Cancer Center, Research Institute, 666-2 Nitona-cho, Chuo-ku, Chiba-shi, Chiba 260-8717, Japan.
Hiroki
H
Nagase
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Thangavel
T
Vaijayanthi
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Rhys D
RD
Taylor
1] Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo, Kyoto 606-8502, Japan [2] Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
Hiroshi
H
Sugiyama
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D015894:Genome, Human; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry; D051379:Mice; D009757:Nylons / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011758:Pyrroles / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation; D000077337:Vorinostat
D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D022661:RNA, Untranslated; D000077337:Vorinostat; D004247:DNA