As in the case of SMA, ASO-mediated lncRNA repression can potentiate the effects
of SSOs by specifically derepressing the expression of the very mRNAs whose
aberrant splicing is targeted for splicing correction [89]. Aside from the demonstration of ASO use to sterically inhibit the SMN-AS1:EZH2 interaction in SMA cells
[90], the use of ASOs to sterically disrupt lncRNA-protein interactions remains to be
explored as a general treatment strategy in other disease models. Any future efforts
to develop ASOs to this end will rely on more comprehensive characterisation of
the structural dynamics of lncRNA-protein interaction. For the time being, it may
be more feasible to develop small molecule inhibitors of interactions between
lncRNAs and epigenetic modifiers, as a recent small molecule screening study
identified compounds from a small panel that could effectively disrupt the interaction of brain-derived neurotrophic factor (BDNF) and EZH2 in cancer cells [96].
As further mechanistic details of lncRNA structural and interactive dynamics
emerge, so must anti-lncRNA drug development co-evolve to quickly exploit
such insights. As the non-coding side of epigenetics continues to be more clearly
illuminated, it is hoped that the front runners of the hotly anticipated novel class
of lncRNA-targeting epidrugs will soon reach the clinic.
Compliance with Ethical Standards
Funding: This study was funded by CERCA Programme/Generalitat de Catalunya, Instituto de
Salud Carlos III co-funded by European Regional Development Funds (ERDF/FEDER) a way to
build Europe (grant number PI10/02267 to M.B.) and COST CM1406 (to M.B.). D.J.H. has
received funding from the People Program (MSCA-ITN-2014-ETN) of the European Union’s
Horizon 2020 Program under Chromatin 3D project (Grant number nº SEP-210147404).
Conflict of Interest: D.J.H. declares that he has no conflict of interest. M.E. declares that he has no
conflict of interest. M.B. declares that she has no conflict of interest.
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Djebali S, Davis CA, Merkel A, Gingeras TR (2012) Landscape of transcription in human
cells. Nature 489:101–108. https://doi.org/10.1038/nature11233
2. Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12:861–874. https://
doi.org/10.1038/nrg3074
3. Iyer MK, Niknafs YS, Malik R et al (2015) The landscape of long noncoding RNAs in the
human transcriptome. Nat Genet 47:199–208. https://doi.org/10.1038/ng.3192
4. Khorkova O, Hsiao J, Wahlestedt C (2015) Basic biology and therapeutic implications of
lncRNA. Adv Drug Deliv Rev 87:15–24. https://doi.org/10.1016/j.addr.2015.05.012
5. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem
81:145–166. https://doi.org/10.1146/annurev-biochem-051410-092902
6. Brockdorff N (2013) Noncoding RNA and Polycomb recruitment. RNA 19:429–442. https://
doi.org/10.1261/rna.037598.112
420
D. Hanly et al.
of SSOs by specifically derepressing the expression of the very mRNAs whose
aberrant splicing is targeted for splicing correction [89]. Aside from the demonstration of ASO use to sterically inhibit the SMN-AS1:EZH2 interaction in SMA cells
[90], the use of ASOs to sterically disrupt lncRNA-protein interactions remains to be
explored as a general treatment strategy in other disease models. Any future efforts
to develop ASOs to this end will rely on more comprehensive characterisation of
the structural dynamics of lncRNA-protein interaction. For the time being, it may
be more feasible to develop small molecule inhibitors of interactions between
lncRNAs and epigenetic modifiers, as a recent small molecule screening study
identified compounds from a small panel that could effectively disrupt the interaction of brain-derived neurotrophic factor (BDNF) and EZH2 in cancer cells [96].
As further mechanistic details of lncRNA structural and interactive dynamics
emerge, so must anti-lncRNA drug development co-evolve to quickly exploit
such insights. As the non-coding side of epigenetics continues to be more clearly
illuminated, it is hoped that the front runners of the hotly anticipated novel class
of lncRNA-targeting epidrugs will soon reach the clinic.
Compliance with Ethical Standards
Funding: This study was funded by CERCA Programme/Generalitat de Catalunya, Instituto de
Salud Carlos III co-funded by European Regional Development Funds (ERDF/FEDER) a way to
build Europe (grant number PI10/02267 to M.B.) and COST CM1406 (to M.B.). D.J.H. has
received funding from the People Program (MSCA-ITN-2014-ETN) of the European Union’s
Horizon 2020 Program under Chromatin 3D project (Grant number nº SEP-210147404).
Conflict of Interest: D.J.H. declares that he has no conflict of interest. M.E. declares that he has no
conflict of interest. M.B. declares that she has no conflict of interest.
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Djebali S, Davis CA, Merkel A, Gingeras TR (2012) Landscape of transcription in human
cells. Nature 489:101–108. https://doi.org/10.1038/nature11233
2. Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12:861–874. https://
doi.org/10.1038/nrg3074
3. Iyer MK, Niknafs YS, Malik R et al (2015) The landscape of long noncoding RNAs in the
human transcriptome. Nat Genet 47:199–208. https://doi.org/10.1038/ng.3192
4. Khorkova O, Hsiao J, Wahlestedt C (2015) Basic biology and therapeutic implications of
lncRNA. Adv Drug Deliv Rev 87:15–24. https://doi.org/10.1016/j.addr.2015.05.012
5. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem
81:145–166. https://doi.org/10.1146/annurev-biochem-051410-092902
6. Brockdorff N (2013) Noncoding RNA and Polycomb recruitment. RNA 19:429–442. https://
doi.org/10.1261/rna.037598.112
420
D. Hanly et al.