TY - JOUR
T1 - The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis
AU - Abdalla, Mohamed Osama Ali
AU - Yamamoto, Tatsuro
AU - Maehara, Kazumitsu
AU - Nogami, Jumpei
AU - Ohkawa, Yasuyuki
AU - Miura, Hisashi
AU - Poonperm, Rawin
AU - Hiratani, Ichiro
AU - Nakayama, Hideki
AU - Nakao, Mitsuyoshi
AU - Saitoh, Noriko
N1 - Funding Information:
We thank all of the members of the Nakao and Saitoh laboratories for discussions and technical assistance. We thank Dr. Gary Felsenfeld (NIH), Dr. Musa Mhlanga (University of Cape Town), and Dr. Yutaka Negishi (University of Cape Town) for critical reading of the manuscript and helpful discussions. We appreciate Dr. Hiroshi Kimura (Tokyo Institute of Technology) for important discussion. We also thank the Advanced Computational Scientific Program of the Research Institute for Information Technology, Kyushu University for providing high-performance computing resources. This work was supported by the JSPS KAKENHI (18H04904, 19H04970 [to K.M.], 18H04802, 18H05527, 19H05244 [to Y.O.], 18H05530 [to I.H.], 18K19479 [to M.N.], and 18H05531, 18K19310 [to N.S.]); JST CREST JPMJCR16G1 [to Y.O.]; Mitsubishi Foundation [to M. N.]; AMED CREST JP16gm0510007 [to M.N.]; The Naito Foundation; Takeda Science Foundation; and The Vehicle Racing Commemorative Foundation [to N.S.]. This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.
AB - MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.
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U2 - 10.1038/s41467-019-11378-4
DO - 10.1038/s41467-019-11378-4
M3 - Article
C2 - 31439835
AN - SCOPUS:85071285883
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3778
ER -
