INTRODUCTION The cell nucleus is not randomly organized Individual - - PowerPoint PPT Presentation

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Mar 30, 2023 161 likes •306 views

GENOMIC ARCHITECTURE : CHROMOSOME KISSING, TRANSCRIPTION FACTORIES AND TRANSLOCATIONS Master in Advanced Genetics - GENOMICS Jos Luis Snchez-Trincado Lpez INTRODUCTION The cell nucleus is not randomly organized Individual chromosomes

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GENOMIC ARCHITECTURE: CHROMOSOME KISSING,

TRANSCRIPTION FACTORIES AND TRANSLOCATIONS

Master in Advanced Genetics - GENOMICS José Luis Sánchez-Trincado López

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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

Bender, M.A. (2012) Lanctôt, C. (2007)

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Spatial co-localization, the so-called gene kissing

REPRESSION

PolycombGroup (PcG) proteins
Both cis and trans regulation
Fab7 regulatory sequences

ACTIVATION

Foci enriched in RNA

pol II (Transcription factories) TRANSCRIPTION

Lanctôt, C. (2007).

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Lanctôt, C. (2007)

So… How does the chromatin manage to get either mobilized or stabilized?

Actin and myosin
RNA-polymerase

holoenzymes

RNAi machinery?

There are two non-exclusive models to explain chromatin rearrangements:

Pre-existing compartments
Self-organization

Movement Fixation

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Spatial organization mapping

Cai, S. (2006) Wong, B. (2011) de Wit, E. (2012)

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TRANSCRIPTION FACTORIES

Chakalova, L. (2005)

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

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TRANSCRIPTION FACTORIES Position effects and specialization

Factories become specialized with the action
f transcription factors (left)
Genomic position affects transcription (right)

Feuerborn, A. (2015) Feuerborn, A. (2015)

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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 identifies the “TRANSLOCATOME”

Osborne, C.S. (2013)

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Shared position within the nucleus for rearranged genes in translocation-derived cancers. Burkitt’s lymphoma is an illustrative case

TRANSCRIPTION FACTORIES Translocation-derived cancers

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

Burkitt’s lymphoma Etoposide

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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
f sequences within the same position, causing transcription

activation or repression.

Transcription

factories constitute a source

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”.

CONCLUSIONS: a summary

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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
f chromosome contact.
Promote the conception of focused anticancer drugs that

can minimize deleterious effects in cancer genes.

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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
n 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.

References

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