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Confused cell signals lead to genetic disorders

The scientific and medical community is working to understand how subtle changes in the LMNA gene cause so many genetic disorders of the nerve, heart and muscles, as well as premature aging.


No other gene works like the LMNA gene. In a new study, Jelena Perovanovic PhD in Bioinformatics, Molecular Biology and Developmental Biology at the National Institutes of Health in Bethesda, Maryland, along with co-author Eric Hoffman PhD, Associate Dean for Research in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, commonly referred to as Binghamton University (BU) or SUNY Binghamton, both believe it has to do with cell "commitment."

From the initial joining of egg and sperm, cells begin dividing into two cells — one remains as the stem cell, with the other to become a particular tissue cell or organ cell type (cell lineage). How to manipulate this act is part and parcel to studying stem cells and creating cell types for regenerative medicine.

Published April 20 in Science Translational Medicine, the paper Laminopathies disrupt epigenomic developmental programs and cell fate, provides a model of cell division and how subtle mutations of the LMNA gene can be disruptive to cell commitment.


"A one-letter change, a one amino acid change in this big protein [LMNA], and we see patients with severe muscle problems. Just a couple letters away, the same amino acid change instead causes loss of fat in other patients.

"The cell must make sure the right areas are taken out of circulation. Taking the wrong area, or not enough areas, or too many areas out of circulation, generates confusion — not giving the cell the right instructions [to perform normally]."


Eric Hoffman PhD, Associate Dean for Research, Binghamton University, School of Pharmacy and Pharmaceutical Sciences, co-author of the study.


The nuclear lamina — a fibrous network organized around the nuclear membrane’s innerside — has both structural and functional roles. It interacts with chromosomes at regions called lamina-associated domains (LADs). The nuclear envelope is the key structure separating animals with organs, like ourselves, from bacteria. Different parts of the genome need to attach to the nuclear envelope — in order to turn off gene functions.


A nuclear membrane, also known as the nuclear envelope, is the double membrane made up of lipids [fats, waxes, sterols, fat-soluble vitamins] that surrounds the genetic material in the nucleolus of eukaryotic cells [organisms whose cells contain a nucleus and other organelles enclosed within membranes].

Image Credit: Wikipedia

Once attachment regions are taken out of genetic circulation (become heterochromatin) -
they are never used again.


The attachment process defines what part of the genome is no longer useful to that particular cell/organ type — discarding any DNA not focused on what the cell is supposed to become. Once a chromosome attaches to the lamina, the cell cyle stops. Therefore, a heart cell will not latter suddenly become a nerve. Discarding superfluous DNA keeps the cell focused on a future plan.

Mutations in LMNA cause Emery-Dreifuss muscular dystrophy (EDMD). Jelena Perovanovic was particularly focused on causes of EDMD and her research now shows that LMNA mutations interfere with lamin A – and the heterochromatin process.

Proper cell differentiation hinges on “the coordinated execution of three key cellular programs,” say the authors. Pluriopotency gives primitive cells the remarkable ability to generate any cell type in the body. But pluripotency must become inactivated by attachment to the lamina to fix a cell to a specific purpose. Once exited out of the cell cycle, a cell stops dividing and in particular cells, myogenesis begins. Myogenesis is a complex and tightly regulated process, which ends in the formation of a multinucleated myofibre with contractile capability — muscle.

Mutations in lamina attachment can disrupt the careful choreography of myogenesis, ending in a slowed exit from the cell cycle, slowed exit from pluripotency, and poorly coordinated terminal differentiation of the newly forming cell.


"We provide a model for how these very subtle changes in a single protein cause such dramatically different clinical problems. Why, because the process of taking parts of the genome out of circulation during [nuclear lamina attachment] assists a cell in making decisions."

Eric Hoffman PhD


Abstract
The nuclear envelope protein lamin A is encoded by the lamin A/C (LMNA) gene, which can contain missense mutations that cause Emery-Dreifuss muscular dystrophy (EDMD) (p.R453W). We fused mutated forms of the lamin A protein to bacterial DNA adenine methyltransferase (Dam) to define euchromatic-heterochromatin (epigenomic) transitions at the nuclear envelope during myogenesis (using DamID-seq). Lamin A missense mutations disrupted appropriate formation of lamin A–associated heterochromatin domains in an allele-specific manner—findings that were confirmed by chromatin immunoprecipitation–DNA sequencing (ChIP-seq) in murine H2K cells and DNA methylation studies in fibroblasts from muscular dystrophy patient who carried a distinct LMNA mutation (p.H222P). Observed perturbations of the epigenomic transitions included exit from pluripotency and cell cycle programs [euchromatin (open, transcribed) to heterochromatin (closed, silent)], as well as induction of myogenic loci (heterochromatin to euchromatin). In muscle biopsies from patients with either a gain- or change-of-function LMNA gene mutation or a loss-of-function mutation in the emerin gene, both of which cause EDMD, we observed inappropriate loss of heterochromatin formation at the Sox2 pluripotency locus, which was associated with persistent mRNA expression of Sox2. Overexpression of Sox2 inhibited myogenic differentiation in human immortalized myoblasts. Our findings suggest that nuclear envelopathies are disorders of developmental epigenetic programming that result from altered formation of lamina-associated domains.


Additional authors: Jelena Perovanovic, Stefania Dell’Orso, Viola F. Gnochi, Jyoti K. Jaiswal, Vittorio Sartorelli, Corinne Vigouroux, Kamel Mamchaoui, Vincent Mouly, Gisèle Bonne and Eric P. Hoffman.

Related material
Genetic suppression

Subtle Changes in Just One Part of the Cell Can Trigger a Cascade of ‘Cellular Misadventures’

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May 2, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Emery-Dreifuss muscular dystrophy (EDMD) is one of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles. It is named for Alan Emery and Fritz Dreifuss, physicians who first described the disorder among a Virginia family in the 1960s.

EDMD usually shows itself by age 10 and is characterized by wasting and weakness of the muscles that make up the shoulders and upper arms and the calf muscles of the legs. Another prominent aspect of EDMD is the appearance of contractures (stiff joints) in the elbows, neck and heels very early in the course of the disease. Finally, and very importantly, a type of heart problem called a conduction block is a common feature of EDMD and requires monitoring.
Image Credit: Muscular Dystrophy Association

 


 

 


 

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