Navigation Links
Successful stem cell differentiation requires DNA compaction, study finds

New research findings show that embryonic stem cells unable to fully compact the DNA inside them cannot complete their primary task: differentiation into specific cell types that give rise to the various types of tissues and structures in the body.

Researchers from the Georgia Institute of Technology and Emory University found that chromatin compaction is required for proper embryonic stem cell differentiation to occur. Chromatin, which is composed of histone proteins and DNA, packages DNA into a smaller volume so that it fits inside a cell.

A study published on May 10, 2012 in the journal PLoS Genetics found that embryonic stem cells lacking several histone H1 subtypes and exhibiting reduced chromatin compaction suffered from impaired differentiation under multiple scenarios and demonstrated inefficiency in silencing genes that must be suppressed to induce differentiation.

"While researchers have observed that embryonic stem cells exhibit a relaxed, open chromatin structure and differentiated cells exhibit a compact chromatin structure, our study is the first to show that this compaction is not a mere consequence of the differentiation process but is instead a necessity for differentiation to proceed normally," said Yuhong Fan, an assistant professor in the Georgia Tech School of Biology.

Fan and Todd McDevitt, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, led the study with assistance from Georgia Tech graduate students Yunzhe Zhang and Kaixiang Cao, research technician Marissa Cooke, and postdoctoral fellow Shiraj Panjwani.

The work was supported by the National Institutes of Health's National Institute of General Medical Sciences (NIGMS), the National Science Foundation, a Georgia Cancer Coalition Distinguished Scholar Award, and a Johnson & Johnson/Georgia Tech Healthcare Innovation Award.

To investigate the impact of linker histones and chromatin folding on stem cell differentiation, the researchers used embryonic stem cells that lacked three subtypes of linker histone H1 -- H1c, H1d and H1e -- which is the structural protein that facilitates the folding of chromatin into a higher-order structure. They found that the expression levels of these H1 subtypes increased during embryonic stem cell differentiation, and embryonic stem cells lacking these H1s resisted spontaneous differentiation for a prolonged time, showed impairment during embryoid body differentiation and were unsuccessful in forming a high-quality network of neural cells.

"This study has uncovered a new, regulatory function for histone H1, a protein known mostly for its role as a structural component of chromosomes," said Anthony Carter, who oversees epigenetics grants at NIGMS. "By showing that H1 plays a part in controlling genes that direct embryonic stem cell differentiation, the study expands our understanding of H1's function and offers valuable new insights into the cellular processes that induce stem cells to change into specific cell types."

During spontaneous differentiation, the majority of the H1 triple-knockout embryonic stem cells studied by the researchers retained a tightly packed colony structure typical of undifferentiated cells and expressed high levels of Oct4 for a prolonged time. Oct4 is a pluripotency gene that maintains an embryonic stem cell's ability to self-renew and must be suppressed to induce differentiation.

"H1 depletion impaired the suppression of the Oct4 and Nanog pluripotency genes, suggesting a novel mechanistic link by which H1 and chromatin compaction may mediate pluripotent stem cell differentiation by contributing to the epigenetic silencing of pluripotency genes," explained Fan. "While a significant reduction in H1 levels does not interfere with embryonic stem cell self-renewal, it appears to impair differentiation."

The researchers also used a rotary suspension culture method developed by McDevitt to produce with high efficiency homogonous 3D clumps of embryonic stem cells called embryoid bodies. Embryoid bodies typically contain cell types from all three germ layers -- the ectoderm, mesoderm and endoderm -- that give rise to the various types of tissues and structures in the body. However, the majority of the H1 triple-knockout embryoid bodies formed in rotary suspension culture lacked differentiated structures and displayed gene expression signatures characteristic of undifferentiated stem cells.

"H1 triple-knockout embryoid bodies displayed a reduced level of activation of many developmental genes and markers in rotary culture, suggesting that differentiation to all three germ layers was affected." noted McDevitt.

The embryoid bodies also lacked the epigentic changes at the pluripotency genes necessary for differentiation, according to Fan.

"When we added one of the deleted H1 subtypes to the embryoid bodies, Oct4 was suppressed normally and embryoid body differentiation continued," explained Fan. "The epigenetic regulation of Oct4 expression by H1 was also evident in mouse embryos."

In another experiment, the researchers provided an environment that would encourage embryonic stem cells to differentiate into neural cells. However, the H1 triple-knockout cells were defective in forming neuronal and glial cells and a neural network, which is essential for nervous system development. Only 10 percent of the H1 triple-knockout embryoid bodies formed neurites and they produced on average eight neurites each. In contrast, half of the normal embryoid bodies produced, on average, 18 neurites.

In future work, the researchers plan to investigate whether controlling H1 histone levels can be used to influence the reprogramming of adult cells to obtain induced pluripotent stem cells, which are capable of differentiating into tissues in a way similar to embryonic stem cells.

Contact: Abby Robinson
Georgia Institute of Technology Research News

Related biology news :

1. Eye-tracking reveals variability in successful social strategies for children with autism
2. Severe congenital disorder successfully treated in a mouse model for the first time
3. Genomic sequences of 2 iconic falconry birds - Peregrine and Saker Falcons- successfully decoded
4. KAISTs successful transfer of green technology
5. Biodegradable mulches successfully control weeds in container-grown arborvitae
6. Teaching skills key to selection of a successful model farmer
7. National Institutes of Health renews successful infectious disease research study
8. Exonhit and BGI announce successful completion of a promising next-generation sequencing project
9. New substance may allow successful transplantation of marginal livers
10. Successful strategy developed to regenerate blood vessels
11. LSUHSC reports first successful salivary stone removal with robotics
Post Your Comments:
Related Image:
Successful stem cell differentiation requires DNA compaction, study finds
(Date:11/12/2015)... Nov. 12, 2015  Arxspan has entered into ... and Harvard for use of its ArxLab cloud-based ... tools. The partnership will support the institute,s efforts ... chemical research information internally and with external collaborators. ... for managing the Institute,s electronic laboratory notebook, compound ...
(Date:11/11/2015)...   MedNet Solutions , an innovative SaaS-based eClinical technology ... pleased to announce that it will be a Sponsor of ... to be held November 17-19 in Hamburg ... of iMedNet , MedNet,s easy-to-use, proven and ... has been able to deliver time and cost savings of ...
(Date:11/10/2015)... NEW YORK , Nov. 10, 2015 /PRNewswire/ ... refers to behavioral biometrics that helps to identify ... prevent fraud. Signature is considered as the secure ... for the identification of a particular individual because ... offers more accurate results especially when dynamic signature ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... --> --> ... Synthesis Market by Product & Services (Primer, Probe, Custom ... RNAi), End-User (Research, Pharmaceutical & Biotech, Diagnostic Labs) - ... is expected to reach USD 1,918.6 Million by 2020 ... of 10.1% during the forecast period. Browse ...
(Date:11/24/2015)... Massachusetts , November 24, 2015 SHPG ... will participate in the Piper Jaffray 27 th Annual Healthcare ... Tuesday, December 1, 2015, at 8:30 a.m. EST (1:30 p.m. GMT). ... , Chief Financial Officer, will participate in the Piper Jaffray 27 ... , NY on Tuesday, December 1, 2015, at 8:30 a.m. ...
(Date:11/24/2015)... CITY , Nov. 24, 2015 /PRNewswire/ - ... "Company") announced today that the remaining 11,000 post-share ... Share Purchase Warrants (the "Series B Warrants") subject ... were exercised on November 23, 2015, which will ... Shares.  After giving effect to the issuance of ...
(Date:11/24/2015)... ... ... InSphero AG, the leading supplier of easy-to-use solutions for production, culture, and ... as Chief Operating Officer. , Having joined InSphero in November 2013 as ... promoted to Head of InSphero Diagnostics in 2014. There she has built up ...
Breaking Biology Technology: