Introduction

Linking the chr21 gene dosage imbalance in Down’s syndrome (DS) with the considerable variability of the DS phenotype has been an elusive goal in the study of trisomy 21 (T21) activity, function, genetics, and epigenetics (Hattori et al. 2000; Antonarakis 2017; Castro et al. 2017; Max Plank Institute 2017; NCBI 2017; Vega Genome Browser 54: Homo sapiens 2017). Interestingly, a single copy gene encoding the 770 amino acid beta amyloid precursor protein, the precursor to the 42 amino acid amyloid beta (Aβ42) peptide that accumulates in both familial and sporadic Alzheimer’s disease (AD) and DS brains is encoded at chr21q21.3; virtually all DS patients exhibit AD-type pathological change as they age, including progressive Aβ42 peptide accumulation (Castro et al. 2017a; Hithersay et al. 2017). Evidence associating a specific gene or chr21 domain to a particular phenotype has been restricted and relatively limited in chr21 genomic studies (Hattori et al. 2000; Antonarakis 2017; Castro et al. 2017; Hithersay et al. 2017). Another understudied and perhaps underappreciated area of T21 gene triplication are the potential contribution of chr21-encoded micro RNAs (miRNAs), their DS-associated increase in abundance (because of the extra chr21 copy—a gene dosage effect), and their enormous potential to shape and regulate the DS transcriptome, and hence alter both pathogenic and global gene expression patterns (Hattori et al. 2000; Li et al. 2012; Ghorai and Ghosh 2014; Hithersay et al. 2017).

miRNAs represent a novel and intriguing group of endogenous small non-protein-coding RNAs (sncRNAs) that are evolutionarily conserved and widely distributed amongst all species so far studied in both the plant and animal kingdoms (Guo et al. 2010; Eichhorn et al. 2014; Hruska-Plochan et al. 2015; Zhao et al. 2015a, b; Hill and Lukiw 2016; Liu et al. 2017). Interestingly, a single miRNA can regulate multiple target genes dispersed throughout all somatic chromosomes, indicating that miRNAs may regulate multiple signaling pathways and participate in numerous physiological and pathological processes. The major mode of action of these sncRNAs is to interact, via base-pair complementarity, with the 3′-untranslated region of their target messenger RNAs (mRNAs), and in doing so decrease the expression of that particular target mRNA, and hence act as negative regulators of target gene expression. Ribosome profiling and RNA sequencing have shown that up-regulated miRNAs act predominantly to decrease their target mRNA levels, and miRNA-mediated destabilization of mRNAs is the main reason for the observed reductions in gene expression that are characteristic of both AD and DS brains (Guo et al. 2010; Codocedo et al. 2016; Liu et al. 2017).

Consisting of 48 million base pairs (Mbps) and representing ~1.5% of total cellular DNA, chr21 contains a relatively low number of identified genes (~225), for example, compared with the 545 genes reported for the 49 Mbp chromosome 22 (chr22; Hattori et al. 2000). Equally under-represented is the small number of just five miRNAs encoded and clustered around the long arm of chr21 spanning the chr21q21.1-chr21q21.3 region (compared to the ~46 miRNAs encoded on chr22; Dunham et al. 1999; “Vega Genome Browser 54: Homo sapiens 2017; http://atlasgeneticsoncology.org/Indexbychrom/idxg_22.html). Chr21 encoded miRNAs include let-7c, miRNA-99a, miRNA-125b, miRNA-155, and miRNA-802. Together specific members of this small miRNA family (i) have been found to be readily detectable in control brains and significantly up-regulated in both AD and DS brains (Zhao et al. 2015a, b; Hill and Lukiw 2016), (ii) are observed to be up-regulated more than gene-dosage effects alone would predict (Li et al. 2012), (iii) includes a subset of miRNAs including miRNA-99a, miRNA-125b, and miRNA-155 that are inducible and under NF-kB regulatory control (Lukiw 2007, 2012; Prasad 2017; unpublished observations), and (iv) are known to down-regulate the expression of key innate-immune regulatory and anti-inflammatory genes in AD and/or DS (Pogue et al. 2010; Lukiw et al. 2012; Maciotta et al. 2013; Hill et al. 2015; Hill and Lukiw 2016; Nadim et al. 2017). For example, gene dosage mediated increases in the chr21-encoded miRNA-155 have been shown in part to down-regulate the expression of complement factor H, an important soluble, innate-immune regulatory glycoprotein in AD and DS tissues and in primary brain cell models of AD, and be centrally involved in pathogenic signaling pathways that include inflammatory neurodegeneration (Li et al. 2012; Lukiw 2012; Zhao et al. 2015a, b; Hill and Lukiw 2016).

Concluding Remarks

As research into the molecular-genetics of DS (T21) progresses, more and more neurological (and non-neurological) diseases have been shown to be significantly linked to the T21 phenotype. This ‘Short Communications’ paper provides four novel findings hitherto unrecognized or undocumented in the research field involving the molecular-genetics of T21: (i) for the first time we point out that the five miRNAs encoded on the extra copy of chromosome 21 in DS have potential to regulate the expression of over 3600 genes (see Table 1 and text), (ii) largely due to the containment of five miRNAs encoded on chromosome 21, and the fact that DS is the most common genetic cause of intellectual disability attributable to a naturally occurring imbalance in gene dosage; this communication provides the first example of what was classically considered a neurological-developmental-dementing disorder as also a serious contributor to the development of disease in other major organ systems including the heart, lung, blood, bladder, prostate, thyroid and circulatory system, GI tract, as well as predisposition to many types of cancer, (iii) for the first time we point out the hitherto unappreciated regulatory potential of chromosome 21 in the development of a very broad clinical spectrum of potentially fatal human disease, and (iv) that further study and analysis of these chr21-encoded miRNAs, their mRNA interactions and induction of pathogenic biological pathways provides a greatly expanded list of potential therapeutic targets which would ultimately define the basis for more effective treatments in the clinical management of secondary maladies associated with development of chr21-linked disease.

Table 1 miRNAs encoded on human chr 21, location, Genbank accession, function/disease association, and references
Full size table

Perhaps most importantly, miRNA–mRNA integration mapping, in depth RNA sequence analysis using complementarity algorithms and bioinformatics evaluation indicate that these five chr21-encoded miRNAs have the remarkable capacity to potentially regulate the expression approximately 3630 protein-coding genes (Table 1). This rather large number of protein-coding genes targeted by chr21-encoded miRNAs and the chr21 miRNA-mediated potential down-regulation of vast numbers of mRNAs may in part explain the tremendous diversity and complexity of human maladies associated with DS. This knowledge should be useful in targeting miRNA-mediated molecular mechanisms that cause or modify the development and propagation of different DS phenotypes. For example, employing anti-miRNA-based therapeutic strategies directed toward a single or a few chr21 specific miRNAs: (i) could be of therapeutic use in the restoration of essential and homeostatic mRNA and gene expression patterns in DS patients, and/or (ii) may ultimately provide more effective treatments in the clinical management of ancillary maladies associated with the T21 phenotype (Lukiw 2013; Antonarakis 2017; Castro et al. 2017; Zhao et al. 2016).