Identifying Putative Promoter Regions of Hermansky‐Pudlak Syndrome Genes by Means of Phylogenetic Footprinting

Abstract

SummaryHPS is an autosomal recessive disorder characterized by oculocutaneous albinism and prolonged bleeding. Eight human genes are described resulting in the HPS subtypes 1-8. Certain HPS proteins combine to form Biogenesis of Lysosomerelated Organelles Complexes (BLOCs), thought to function in the formation of intracellular vesicles such as melanosomes, platelet dense bodies, and lytic granules. Specifically, BLOC-2 contains the HPS3, HPS5 and HPS6 proteins. We used phylogenetic footprinting to identify conserved regions in the upstream sequences of HPS3, HPS5 and HPS6. These conserved regions were verified to have in vitro transcription activation activity using luciferase reporter assays. Transcription factor binding site analyses of the regions identified 52 putative sites shared by all three genes. When analysis was limited to the conserved footprints, seven binding sites were found shared among all three genes: Pax-5, AIRE, CACD, ZF5, Zic1, E2F and Churchill. The HPS3 conserved upstream region was sequenced in four patients with decreased fibroblast HPS3 RNA levels and only one HPS3 mutation in the coding exons and surrounding exon/intron boundaries; no mutation was found. These findings illustrate the power of phylogenetic footprinting for identifying potential regulatory regions in non-coding sequences and define the first putative promoter elements for any HPS genes.

Profiling of the BRCA1 transcriptome through microarray and ChIP-chip analysis

“…In addition, binding sites for ZF5 are enriched in the genetic promoters of clock-regulated genes, as have binding sites for the known BRCA1 interacting TFs; E2F, AP-1 and NF-Y, SP1 and Oct-1 ( 14 , 15 , 47 ). ZF5 binding sites are also enriched in the promoters of Hermansky–Pudlak syndrome genes HPS3, HPS5 and HPS6 ( 48 ); interestingly, this study also found enrichment of Churc1 binding sites within the promoters of these genes. Taken together, this suggests that BRCA1, Churc1, ZF5 and the other BRCA1 interacting TFs mentioned above may exist as a single and/or multiple complex(es) involved in the transcriptional regulation of various genes.…”

Hermansky–Pudlak syndrome: pigmentary and non‐pigmentary defects and their pathogenesis

“…A transcription factor EB (TFEB) has been reported to be the master regulator of lysosomal biogenesis (Sardiello et al, 2009). Putative promoter regions of HPS genes may be regulated by TFEB or other transcription factors (Palmieri et al, 2011;Stanescu et al, 2009). The well-known function of lysosomes is the degradation of transported cargoes via the endo-lysosomal-trafficking system.…”

Novel Variants of <i>HPS6</i> Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of <i>HPS6</i> Variants

“…Human Hermansky-Pudlak syndrome 6 (HPS6) is located on human chromosome 10q24.32, and it consists of only one exon (NM_024747), which is ubiquitously expressed in a variety of tissues [13][14][15]. The transcript size of HPS6 is around 2.6 kb, and its open reading frame encodes 775 amino acids, making up an 83.0 kDa protein (NP_079023) without homology to other human proteins [16,17].…”