The HELLS gene consists of 22 exons spanning 57104 base pairs. It is highly expressed in embryonic stem cells, proliferating lymphoid cells/tissue, and germ cells. In stem cells, expression decreases upon differentiation. HELLS is additionally expressed at a lower level in many tissues of the developing embryo. In normal adult somatic tissue, expression is low with the exception of proliferating lymphocytes.

The HELLS gene produces a transcript of 3163 bp. Ten alternatively spliced isoforms have been detected. The functional relevance of most of these splice variants is currently unknown. One, variant 1 containing a 44 ntd insertion between exons 3 and 4, creates an additional exon and has been associated with non-small cell lung cancer (NSCLC) (Yano et al., 2004). An additional variant, variant 9, contains a 75 ntd deletion in exon 18 and has been associated with acute myelogenous leukemia an acute lymphoblastic leukemia (Lee et al., 2000).

None.

HELLS protein consists of 838 amino acids with a predicted size of 97 kD. Since Lsh is a member of the SNF2 chromatin remodeling protein family, it contains the ATP binding and C-terminal helicase domains of this subfamily of helicases.

Nuclear.

HELLS functions as a chromatin remodeling family member linking multiple epigenetic mechanisms including histone modifications and DNA methylation (Dennis et al., 2001; Yan et al., 2003a; Yan et al., 2003b; Huang et al., 2004; Fan et al., 2005; Zhu et al., 2006; Xi et al., 2007; Myant et al., 2008). Knockout mice die perinatally with defects in lymphocyte proliferation, embryonic growth, and kidney development (Geiman et al., 2001; Geiman and Muegge, 2000). Loss leads to global DNA methylation changes including global hypomethylation at repetive sequences, as well as both hypo and hypermethylation of single copy genes (Myant et al., 2011; Tao et al., 2011b; Dunican et al., 2013; Yu et al., 2014). HELLS has been identified as a marker of mammalian stem cells with expression decreasing upon differentiation. Reduction in expression of HELLS leads to prolonged expresssion of stem cell genes implicating this protein as having a role in stem cell gene silencing (Xi et al., 2009). HELLS has been also implicated in DNA repair (Burrage et al., 2012). HELLS is additionally involved in meiosis with its loss leading to reduced proliferation and differentiation of germ cells with defects in synapsis (de la Fuente et al., 2006; Zeng et al., 2011).

HELLS exhibits homology with other SNF2 family members like SNF2H, SNF2L, CHD1, CHD2, CHD3, CHD4, CHD5, CHD6, CHD7, CHD8, CHD9, BRG1, and BRAHMA. While other SNF2 family members contain additional domains such as chromodomains, bromodomains, BRK, PHD, and RING fingers, HELLS protein does not. Because of this lack of additional domains, Lsh does not fit into any of the other subfamilies of SNF2 members but appears to represent a distinct subfamily of SNF2 factors. By homology, it is most closely related to the CHD and SNF2H/L (ISWI) subfamily.

Hells^tm1Kmu
There are two mutant mouse models of HELLS. The original knockout mouse generated by the Muegge lab (Hells^tm1Kmu) deleting the helicase domains of I, Ia, and part of two that are included in exons 6 and 7. These mutant mice die perinatally with embryonic growth retardation (Geiman et al., 2001). These null embryos have kidney defects such as necrosis and globule formation in tubules (Geiman et al., 2001). Murine embryonic fibroblasts display early senescence in culture and mitotic defects (Fan et al., 2003). Since HELLS is highly expressed in developing and activated lymphoid tissue, lymphoid development and function was studied using a radiation chimera. Null embryos display lymphoid defects in thymocyte development with a partial blockage in transitioning from CD4/CD8 double negative to double positive T lymphocytes. This partial arrest in lymphocyte development leads to a reduction in mature T and B lymphocytes (Geiman et al., 2000). In addition, activation of lymphocytes leads to apoptosis intead of cell proliferation (Geiman et al., 2000). Molecular studies on this mouse led to identifying HELLS as a gene necessary for DNA methylation and important for correct chromatin packaging and histone methylation (Dennis et al., 2001; Yan et al., 2003b ; Huang et al., 2004; Myant et al., 2011; Tao et al., 2011b; Yu et al., 2014).
Hells^tm1Rarc
Another mutant mouse model of Hells was developed in the Arceci lab designated Hells^tm1Rarc. This mouse model was generated from a hypomorphic allele of HELLS by deleting exons 10, 11, and 12 (Sun et al., 2004). The deleted section includes several helicase domains of HELLS (III, IV, and part of II) but not the ATPase domain. This mutant mouse also shows growth retardation but approximately 40% of mice survive to several weeks of age unlike the Muegge mouse model which die at birth. Additionally, these mice exhibit signs of premature aging with defects such as graying hair and balding, low fat deposition, and unstable gate among others (Sun et al., 2004). The premature aging defects seen in this mouse model are likely the result of replicative senescence caused by increased expression of the p16 tumor suppressor gene in these HELLS mutant mice. Molecular analysis demonstrated profound DNA methylation loss and aberrant expression of repeat sequences (Sun et al., 2004; Dunican et al., 2013).