Juxtaposition of heterochromatic and euchromatic regions by chromosomal translocation mediates a heterochromatic long-range position effect associated with a severe neurological phenotype

Palma Finelli, Silvia Maria Sirchia, Maura Masciadri, Milena Crippa, Maria Paola Recalcati, Daniela Rusconi, Daniela Giardino, Laura Monti, Francesca Cogliati, Francesca Faravelli, Federica Natacci, Leonardo Zoccante, Bernardo Dalla Bernardina, Silvia Russo, Lidia Larizza

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: The term "position effect" is used when the expression of a gene is deleteriously affected by an alteration in its chromosomal environment even though the integrity of the protein coding sequences is maintained. We describe a patient affected by epilepsy and severe neurodevelopment delay carrying a balanced translocation t(15;16)(p11.2;q12.1)dn that we assume caused a position effect as a result of the accidental juxtaposition of heterochromatin in the euchromatic region. Results: FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15). Conclusions: To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.

Original languageEnglish
Article number16
JournalMolecular Cytogenetics
Volume5
Issue number1
DOIs
Publication statusPublished - 2012

Fingerprint

Genetic Translocation
Heterochromatin
Genes
Phenotype
Euchromatin
Gene Expression
Chromatin Immunoprecipitation
Interphase
Satellites
Drosophila
Real-Time Polymerase Chain Reaction
Epilepsy
Chromosomes
Chromatin
Proteins

Keywords

  • Balanced translocation
  • Epigenetic modification
  • Gene expression perturbation
  • Heterochromatin
  • Position effect

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Genetics(clinical)
  • Biochemistry
  • Molecular Medicine
  • Biochemistry, medical

Cite this

Juxtaposition of heterochromatic and euchromatic regions by chromosomal translocation mediates a heterochromatic long-range position effect associated with a severe neurological phenotype. / Finelli, Palma; Sirchia, Silvia Maria; Masciadri, Maura; Crippa, Milena; Recalcati, Maria Paola; Rusconi, Daniela; Giardino, Daniela; Monti, Laura; Cogliati, Francesca; Faravelli, Francesca; Natacci, Federica; Zoccante, Leonardo; Bernardina, Bernardo Dalla; Russo, Silvia; Larizza, Lidia.

In: Molecular Cytogenetics, Vol. 5, No. 1, 16, 2012.

Research output: Contribution to journalArticle

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T1 - Juxtaposition of heterochromatic and euchromatic regions by chromosomal translocation mediates a heterochromatic long-range position effect associated with a severe neurological phenotype

AU - Finelli, Palma

AU - Sirchia, Silvia Maria

AU - Masciadri, Maura

AU - Crippa, Milena

AU - Recalcati, Maria Paola

AU - Rusconi, Daniela

AU - Giardino, Daniela

AU - Monti, Laura

AU - Cogliati, Francesca

AU - Faravelli, Francesca

AU - Natacci, Federica

AU - Zoccante, Leonardo

AU - Bernardina, Bernardo Dalla

AU - Russo, Silvia

AU - Larizza, Lidia

PY - 2012

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N2 - Background: The term "position effect" is used when the expression of a gene is deleteriously affected by an alteration in its chromosomal environment even though the integrity of the protein coding sequences is maintained. We describe a patient affected by epilepsy and severe neurodevelopment delay carrying a balanced translocation t(15;16)(p11.2;q12.1)dn that we assume caused a position effect as a result of the accidental juxtaposition of heterochromatin in the euchromatic region. Results: FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15). Conclusions: To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.

AB - Background: The term "position effect" is used when the expression of a gene is deleteriously affected by an alteration in its chromosomal environment even though the integrity of the protein coding sequences is maintained. We describe a patient affected by epilepsy and severe neurodevelopment delay carrying a balanced translocation t(15;16)(p11.2;q12.1)dn that we assume caused a position effect as a result of the accidental juxtaposition of heterochromatin in the euchromatic region. Results: FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15). Conclusions: To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.

KW - Balanced translocation

KW - Epigenetic modification

KW - Gene expression perturbation

KW - Heterochromatin

KW - Position effect

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