Length-dependent gene misexpression is associated with Alzheimer\u2019s disease progression

Shahar Barbash,Thomas P Sakmar

doi:10.1038/s41598-017-00250-4

Shahar Barbash, Thomas P Sakmar

Open Access

https://doi.org/10.1038/s41598-017-00250-4

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Journal: Scientific Reports	Publication Date: Mar 15, 2017
Citations: 15	License type: open-access

Affiliation: Rockefeller University, Karolinska Institutet

Abstract

Recent reports show transcription preference for long genes in neuronal tissues compared with non-neuronal tissues, and a gene-length dependent change in expression in the neurodevelopmental disease Rett syndrome (RTT). Whether the gene-length dependent changes in expression seen in RTT might also be seen in neurodegenerative diseases is not yet known. However, a reasonable hypothesis is that similar effects might be seen in neurodegenerative diseases as well as in RTT since a common general feature of both illnesses involves progressive dysfunction of synapses. Here, we demonstrate a clear length-dependent gene misexpression in the most prevalent neurodegenerative disease, Alzheimer’s disease. We show that the effect is associated with disease progression and can be attributed specifically to neurons. In particular, we observed gene length-dependent down regulation on the level of the whole tissue and gene length-dependent up regulation on the level of single cells. Our analysis shows that a gene-length effect on expression can be found in degenerative neurological illnesses, such as Alzheimer’s disease. Additional investigation to elucidate the precise mechanism underlying gene-length dependent changes in expression is warranted.

Highlights

In principle, length-dependent gene expression effects might be measured at the level of whole tissues, or at the level of specific cell populations within a tissue
We examined the genome-wide change in gene expression as a function of gene length in AD samples in which cell death is most robust and widespread similar to Gabel et al.[1]
Length-dependent effect on gene expression in AD could be the outcome of loss of neurons, which will lead to a change in ratio between cell populations, or it could be the outcome of a specific change in transcription of long genes in AD neurons, or it could be a mixture between the two

Summary

Introduction

Length-dependent gene expression effects might be measured at the level of whole tissues, or at the level of specific cell populations within a tissue. While previous studies reported a gene-length dependent expression based on analysis of whole tissues from mouse and human samples, and separately based on single-cell analysis from cell lines[1, 4], we searched for this effect in specific cell populations from adult human brain dataset that includes 466 cells (GSE6783511), to examine Mean expression of genes (log[10] transformed) binned according to gene length for neurons, astrocytes and oligodendrocytes from human adult brain (n = 466 cells in total).

Results

Conclusion