Breakthrough may help treat degenerative disease

The most amazing property of embryonic stem cells is their capability of renewing themselves an infinite number of times and differentiating into every type of mature cell in the body – meaning they have the potential of serving as the “factory” for producing healthy tissues to replace sick ones. But until now, scientists did not know the secret behind this pluripotency, which if revealed could eventually lead to their use to implant healthy new cells into humans suffering from degenerative diseases – from Parkinson’s and Alzheimer’s disease to diabetes.

Doctoral student Shai Melcer and colleagues in the lab of Hebrew University geneticist Dr. Eran Meshorer have just published their research in the prestigious journal Nature Communications, reporting how they identified the processes that turn human embryonic stem cells into any type of body cell.

The article titled “Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation” discusses how the team combined molecular, microscopic and genomic approaches and focused on epigenetic pathways, which cause biological changes without a corresponding change in the DNA sequence and are specific to embryonic stem cells.

The molecular basis for epigenetic mechanisms is chromatin, the combination of DNA and proteins that make up the contents of the nucleus of a cell.

Chromatin’s main functions are to package DNA into a smaller volume to fit in the cell, strengthen the DNA to allow cell division and prevent harm to the DNA, and control gene expression and DNA replication. The primary protein components of chromatin are histones that compact the DNA.

In what is described by Hebrew University as “groundbreaking research,” Melcer studied the mechanisms that support an “open” chromatin conformation in embryonic stem cells. The team found that chromatin is less condensed in embryonic stem cells, allowing them the flexibility or “functional plasticity” to turn into any kind of cell.

A distinct pattern of chemical modifications of chromatin structural proteins (referred to as the acetylation and methylation of histones) enables a looser chromatin configuration in embryonic stem cells. During the early stages of differentiation, this pattern changes to facilitate chromatin compaction.

They also found that a nuclear lamina protein called lamin A is part of the secret.

In all differentiated cell types, lamin A binds compacted domains of chromatin and anchors them to the cell’s nuclear envelope. Lamin A is absent from embryonic stem cells and this may enable the freer, more dynamic chromatin state in the cell nucleus. The authors believe that chromatin plasticity is tantamount to functional plasticity, since chromatin is made up of DNA that includes all genes and codes for all proteins in any living cell. Understanding the mechanisms that regulate chromatin function will in the future enable intelligent manipulations of embryonic stem cells.

“If we can apply this new understanding about the mechanisms that give embryonic stem cells their plasticity, then we can increase or decrease the dynamics of the proteins that bind DNA and thereby increase or decrease the cells’ differentiation potential,” concluded Meshorer.