Local gene density predicts the spatial position of genetic loci in the interphase nucleus

Andrea E. Murmann; Juntao Gao; Marissa Encinosa; Mathieu Gautier; Marcus E. Peter; Roland Eils; Peter Lichter; Janet D. Rowley

doi:10.1016/j.yexcr.2005.07.020

Local gene density predicts the spatial position of genetic loci in the interphase nucleus

Andrea E. Murmann, Juntao Gao, Marissa Encinosa, Mathieu Gautier, Marcus E. Peter, Roland Eils, Peter Lichter^*, Janet D. Rowley

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

Specific chromosomal translocations are hallmarks of many human leukemias. The basis for these translocation events is poorly understood, but it has been assumed that spatial positioning of genes in the nucleus of hematopoietic cells is a contributing factor. Analysis of the nuclear 3D position of the gene MLL, frequently involved in chromosomal translocations and five of its translocation partners (AF4, AF6, AF9, ENL and ELL), and two control loci revealed a characteristic radial distribution pattern in all hematopoietic cells studied. Genes in areas of high local gene density were found positioned towards the nuclear center, whereas genes in regions of low gene density were detected closer to the nuclear periphery. The gene density within a 2 Mbp window was found to be a better predictor for the relative positioning of a genomic locus within the cell nucleus than the gene density of entire chromosomes. Analysis of the position of MLL, AF4, AF6 and AF9 in cell lines carrying chromosomal translocations involving these genes revealed that the position of the normal genes was different from that of the fusion genes, and this was again consistent with the changes in local gene density within a 2 Mbp window. Thus, alterations in gene density directly at translocation junctions could explain the change in the position of affected genes in leukemia cells.

Original language	English (US)
Pages (from-to)	14-26
Number of pages	13
Journal	Experimental Cell Research
Volume	311
Issue number	1
DOIs	https://doi.org/10.1016/j.yexcr.2005.07.020
State	Published - Nov 15 2005

Funding

We thank Drs. Pamela Strissel, Reiner Strick, Markus O. Scheuermann, James Fackenthal and Isabelle Lucas for their helpful comments. We are grateful to Dr. Michael J. Thirman for his help in locating cell lines and identification of clones for the genes ENL and ELL . We thank Dr. Michelle LeBeau for making the 11365 cell line available for this project, Aparna Palakodeti for sharing her expertise in synchronization of 11365 cells and Yanwen Jiang for sharing his mathematical knowledge. This research was supported by National Institutes of Health/National Cancer Institute Grants CA 40046 and CA 84405 (both to J.D.R.) and the G. Harold and Leila Y. Mathers Charitable Foundation (to J.D.R.) and by the Deutsche Forschungsgemeinschaft (DFG Li 406/5-3).

Keywords

Gene density
MLL
Nuclear organization
Translocation

ASJC Scopus subject areas

Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.yexcr.2005.07.020

Cite this

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title = "Local gene density predicts the spatial position of genetic loci in the interphase nucleus",

abstract = "Specific chromosomal translocations are hallmarks of many human leukemias. The basis for these translocation events is poorly understood, but it has been assumed that spatial positioning of genes in the nucleus of hematopoietic cells is a contributing factor. Analysis of the nuclear 3D position of the gene MLL, frequently involved in chromosomal translocations and five of its translocation partners (AF4, AF6, AF9, ENL and ELL), and two control loci revealed a characteristic radial distribution pattern in all hematopoietic cells studied. Genes in areas of high local gene density were found positioned towards the nuclear center, whereas genes in regions of low gene density were detected closer to the nuclear periphery. The gene density within a 2 Mbp window was found to be a better predictor for the relative positioning of a genomic locus within the cell nucleus than the gene density of entire chromosomes. Analysis of the position of MLL, AF4, AF6 and AF9 in cell lines carrying chromosomal translocations involving these genes revealed that the position of the normal genes was different from that of the fusion genes, and this was again consistent with the changes in local gene density within a 2 Mbp window. Thus, alterations in gene density directly at translocation junctions could explain the change in the position of affected genes in leukemia cells.",

keywords = "Gene density, MLL, Nuclear organization, Translocation",

author = "Murmann, \{Andrea E.\} and Juntao Gao and Marissa Encinosa and Mathieu Gautier and Peter, \{Marcus E.\} and Roland Eils and Peter Lichter and Rowley, \{Janet D.\}",

note = "Funding Information: We thank Drs. Pamela Strissel, Reiner Strick, Markus O. Scheuermann, James Fackenthal and Isabelle Lucas for their helpful comments. We are grateful to Dr. Michael J. Thirman for his help in locating cell lines and identification of clones for the genes ENL and ELL . We thank Dr. Michelle LeBeau for making the 11365 cell line available for this project, Aparna Palakodeti for sharing her expertise in synchronization of 11365 cells and Yanwen Jiang for sharing his mathematical knowledge. This research was supported by National Institutes of Health/National Cancer Institute Grants CA 40046 and CA 84405 (both to J.D.R.) and the G. Harold and Leila Y. Mathers Charitable Foundation (to J.D.R.) and by the Deutsche Forschungsgemeinschaft (DFG Li 406/5-3). ",

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doi = "10.1016/j.yexcr.2005.07.020",

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T1 - Local gene density predicts the spatial position of genetic loci in the interphase nucleus

AU - Murmann, Andrea E.

AU - Gao, Juntao

AU - Encinosa, Marissa

AU - Gautier, Mathieu

AU - Peter, Marcus E.

AU - Eils, Roland

AU - Lichter, Peter

AU - Rowley, Janet D.

N1 - Funding Information: We thank Drs. Pamela Strissel, Reiner Strick, Markus O. Scheuermann, James Fackenthal and Isabelle Lucas for their helpful comments. We are grateful to Dr. Michael J. Thirman for his help in locating cell lines and identification of clones for the genes ENL and ELL . We thank Dr. Michelle LeBeau for making the 11365 cell line available for this project, Aparna Palakodeti for sharing her expertise in synchronization of 11365 cells and Yanwen Jiang for sharing his mathematical knowledge. This research was supported by National Institutes of Health/National Cancer Institute Grants CA 40046 and CA 84405 (both to J.D.R.) and the G. Harold and Leila Y. Mathers Charitable Foundation (to J.D.R.) and by the Deutsche Forschungsgemeinschaft (DFG Li 406/5-3).

PY - 2005/11/15

Y1 - 2005/11/15

N2 - Specific chromosomal translocations are hallmarks of many human leukemias. The basis for these translocation events is poorly understood, but it has been assumed that spatial positioning of genes in the nucleus of hematopoietic cells is a contributing factor. Analysis of the nuclear 3D position of the gene MLL, frequently involved in chromosomal translocations and five of its translocation partners (AF4, AF6, AF9, ENL and ELL), and two control loci revealed a characteristic radial distribution pattern in all hematopoietic cells studied. Genes in areas of high local gene density were found positioned towards the nuclear center, whereas genes in regions of low gene density were detected closer to the nuclear periphery. The gene density within a 2 Mbp window was found to be a better predictor for the relative positioning of a genomic locus within the cell nucleus than the gene density of entire chromosomes. Analysis of the position of MLL, AF4, AF6 and AF9 in cell lines carrying chromosomal translocations involving these genes revealed that the position of the normal genes was different from that of the fusion genes, and this was again consistent with the changes in local gene density within a 2 Mbp window. Thus, alterations in gene density directly at translocation junctions could explain the change in the position of affected genes in leukemia cells.

AB - Specific chromosomal translocations are hallmarks of many human leukemias. The basis for these translocation events is poorly understood, but it has been assumed that spatial positioning of genes in the nucleus of hematopoietic cells is a contributing factor. Analysis of the nuclear 3D position of the gene MLL, frequently involved in chromosomal translocations and five of its translocation partners (AF4, AF6, AF9, ENL and ELL), and two control loci revealed a characteristic radial distribution pattern in all hematopoietic cells studied. Genes in areas of high local gene density were found positioned towards the nuclear center, whereas genes in regions of low gene density were detected closer to the nuclear periphery. The gene density within a 2 Mbp window was found to be a better predictor for the relative positioning of a genomic locus within the cell nucleus than the gene density of entire chromosomes. Analysis of the position of MLL, AF4, AF6 and AF9 in cell lines carrying chromosomal translocations involving these genes revealed that the position of the normal genes was different from that of the fusion genes, and this was again consistent with the changes in local gene density within a 2 Mbp window. Thus, alterations in gene density directly at translocation junctions could explain the change in the position of affected genes in leukemia cells.

KW - Gene density

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KW - Nuclear organization

KW - Translocation

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Local gene density predicts the spatial position of genetic loci in the interphase nucleus

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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