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GENOMIC ARCHITECTURE: CHROMOSOME KISSING,
TRANSCRIPTION FACTORIES AND TRANSLOCATIONS
Master in Advanced Genetics - GENOMICS
José Luis Sánchez-Trincado López
INTRODUCTION
The cell nucleus is not randomly organized
Individual chromosomes occupy distinct
positions
within
the
nucleus:
chromosome territories
Transcription regulation depends upon
genomic regions repositioning
Lanctôt, C. (2007)
Bender, M.A. (2012)
Spatial co-localization, the so-called
gene kissing
TRANSCRIPTION
REPRESSION
- Polycomb Group (PcG) proteins
- Both cis and trans regulation
- Fab7 regulatory sequences
Lanctôt, C. (2007).
ACTIVATION
- Foci enriched in RNA
pol II (Transcription
factories)
So… How does the chromatin
manage to get either mobilized or
stabilized?
- Actin and myosin
- RNA-polymerase
holoenzymes
Movement
- RNAi machinery?
Fixation
There are two non-exclusive models to
explain chromatin rearrangements:
- Pre-existing compartments
- Self-organization
Lanctôt, C. (2007)
Spatial organization mapping
Wong, B. (2011)
de Wit, E. (2012)
Cai, S. (2006)
TRANSCRIPTION FACTORIES
Transcription factories describe the discrete sites where
transcription occurs (in the nucleus). It contains at least
two active polymerases and two DNA templates
- Polymerase concentration: about 1000 fold
higher
- Even 30 polymerase working at a time
together
- From 50 to 500nm in width
- Tethered to nuclear matrix
Chakalova, L. (2005)
TRANSCRIPTION FACTORIES
Position effects and specialization
- Factories become specialized with the action
of transcription factors (left)
- Genomic position affects transcription (right)
Feuerborn, A. (2015)
Feuerborn, A. (2015)
TRANSCRIPTION FACTORIES
A source of translocations
Gene clustering à Consequences on
genome stability
Incorrect rearrangement à translocation
Genomic juxtaposition: before or after
DNA damage?
Rearrangements sequencing
the “TRANSLOCATOME”
identifies
Osborne, C.S. (2013)
TRANSCRIPTION FACTORIES
Translocation-derived cancers
Shared position within the nucleus for
rearranged genes in translocation-derived
cancers.
Burkitt’s lymphoma is an illustrative case
Burkitt’s lymphoma
Programmed DNA break and repair is an integral
part of the transcription process à topoisomerase
Topoisomerase 2B inhibitors (etoposide) spark off
therapy-related second cancers
Etoposide
CONCLUSIONS: a summary
• Nuclear periphery and heterochromatin vicinity areas share a
decreased mobility and are genomic silencing regions, while the
centre is dynamic and transcriptionally active.
• Gene kissing is the intra (cis) or interchromosomal (trans) overlap
of sequences within the same position, causing transcription
activation or repression.
• Transcription factories constitute a source of genomic
rearrangements and translocations. Many of them are responsible
for the arise of cancer.
• New genome-wide technologies are being applied to tease
apart how DNA sequences interact, thereby helping to build up
the human “translocatome”.
DISCUSSION AND FURTHER INSIGHTS
• As a main challenge, unveil how 1D sequence information
specifies 3D architecture and organization.
• Distinguish between sequence-dependent and epigenetics
determinants of chromatin organization and dynamics.
• Develop unbiased methods for genome wide identification
of chromosome contact.
• Promote the conception of focused anticancer drugs that
can minimize deleterious effects in cancer genes.
References
• Lanctôt, C., Cheutin, T., Cremer, M., Cavalli, G. and Cremer, T. (2007).
Dynamic genome architecture in the nuclear space: regulation of gene
expression in three dimensions. Nature Reviews Genetics; 8:104-115.
• Cavalli, G. (2007). Chromosome kissing. Current Opinion in Genetics &
Development; 17:443-450.
• Feuerborn, A. and Cook, P.R. (2015). Why the activity of a gene depends
on its neighbors. Trends in Genetics; 31(9):483-490.
• Osborne, C.S. (2014). Molecular pathways: transcription factories and
chromosomal translocations. Clinical Cancer Research; 20(2):296-300.
• Ezoe, S. (2012). Secondary leukemia associated with the anti-cancer
agent, etoposide, a topoisomerase II inhibitor. International Journal of
Environmental Research and Public Health; 9:2444-2453.
Thank you
for your
attention!
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