non-coding RNA Review The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases Liming Chen 1, Yifan Bao 1, Suzhen Jiang 1,2 and Xiao-bo Zhong 1,* 1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA; [email protected] (L.C.); [email protected] (Y.B.); [email protected] (S.J.) 2 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 51006, China * Correspondence: [email protected]; Tel.: +01-860-486-3697 Received: 25 May 2020; Accepted: 22 June 2020; Published: 24 June 2020 Abstract: Long noncoding RNAs (lncRNAs) are RNAs with a length of over 200 nucleotides that do not have protein-coding abilities. Recent studies suggest that lncRNAs are highly involved in physiological functions and diseases. lncRNAs HNF1α-AS1 and HNF4α-AS1 are transcripts of lncRNA genes HNF1α-AS1 and HNF4α-AS1, which are antisense lncRNA genes located in the neighborhood regions of the transcription factor (TF) genes HNF1α and HNF4α, respectively. HNF1α-AS1 and HNF4α-AS1 have been reported to be involved in several important functions in human physiological activities and diseases. In the liver, HNF1α-AS1 and HNF4α-AS1 regulate the expression and function of several drug-metabolizing cytochrome P450 (P450) enzymes, which also further impact P450-mediated drug metabolism and drug toxicity. In addition, HNF1α-AS1 and HNF4α-AS1 also play important roles in the tumorigenesis, progression, invasion, and treatment outcome of several cancers. Through interacting with different molecules, including miRNAs and proteins, HNF1α-AS1 and HNF4α-AS1 can regulate their target genes in several different mechanisms including miRNA sponge, decoy, or scaffold. The purpose of the current review is to summarize the identified functions and mechanisms of HNF1α-AS1 and HNF4α-AS1 and to discuss the future directions of research of these two lncRNAs. Keywords: lncRNA; HNF1α-AS1; HNF4α-AS1; cancer; cytochrome P450 1. Introduction The advancement of next-generation sequencing techniques makes it possible to investigate the human genome in a clearer and more detailed aspect. In addition to the coding genes, the noncoding genes, which actually take up the majority of the human genome, have also been investigated [1]. The transcripts of noncoding genes are defined as noncoding RNAs (ncRNAs). Initially, ncRNAs were believed to have no protein coding function as they do not have protein-coding open-reading frames (ORFs). However, this idea was challenged by several recent findings, showing that some ncRNAs can generate microproteins/small peptides, which gave rise to a new insight into the ncRNA functions [2,3]. Along with the progress in the identification of all kinds of ncRNAs, the studies focusing on the functions and mechanisms of ncRNAs are also boosting. Long ncRNAs (lncRNAs) are a group of ncRNAs with more than 200 nt in length [4]. lncRNAs are found to be highly involved in the regulation of gene expression and functions. This feature of lncRNAs makes them also important for many biological and physiological processes in human and other organisms. Up to date, several lncRNA databases have been established to assist the study of lncRNAs, Non-coding RNA 2020, 6, 24; doi:10.3390/ncrna6020024 www.mdpi.com/journal/ncrna Non-codingNon-Coding RNA RNA2020 2020, 6, ,6 24, x FOR PEER REVIEW 2 ofof 2122 lncRNAs, including the GENCODE, LNCipedia, ENCODE, and NONCODE [5–8]. According to the includingGENCODE the database, GENCODE, 17,960 LNCipedia, lncRNAs ENCODE, have been and a NONCODEnnotation in [5 –the8]. human According genome to the GENCODEin 2020 [5]. database,However, 17,960 compared lncRNAs to the have large been number annotation of inan thenotated human lncRNAs, genome infar 2020 fewer [5]. lncRNAs However, have compared been tofunctionally the large number characterized of annotated and understood. lncRNAs, far A fewerhuge knowledge lncRNAs have gap beenremains functionally in understanding characterized how andlncRNAs understood. can impact A huge on human knowledge health. gap remains in understanding how lncRNAs can impact on humanHepatocyte health. nuclear factor 1 alpha-antisense-1 (HNF1α-AS1) and HNF4α-antisense-1 (HNF4α- AS1)Hepatocyte are two recently nuclear factoridentified 1 alpha-antisense-1 lncRNAs in human. (HNF1α -AS1)They andare HNF4namedα-antisense-1 based on their (HNF4 genomicα-AS1) arelocations, two recently where identifiedthe noncoding lncRNAs genes in HNF1 human.α-AS1 They andare HNF4 namedα-AS1 based are located on their next genomic to two important locations, wheretranscription the noncoding factor (TF) genes genesHNF1 HNF1α-AS1αand andHNF4 HNF4α-AS1α andare are located transcribed next to in two the important opposite transcription direction on factorthe antisense (TF) genes strand.HNF1 Severalα and HNF4specialα andfunctions are transcribed and mechanisms in the opposite of these direction two lncRNAs on the have antisense been strand.found in Several normal special physiologic functions activities and mechanisms and abnormal of these diseases. two lncRNAs In the have current been article, found inthe normal major physiologicfindings of activitiesHNF1α-AS1 and and abnormal HNF4α diseases.-AS1 are In summarized the current and article, the the future major directions findings of of studies HNF1α about-AS1 andthese HNF4 two lncRNAsα-AS1 are are summarized discussed. and the future directions of studies about these two lncRNAs are discussed. 2. Neighborhood Antisense lncRNAs HNF1α-AS1 and HNF4α-AS1 2. Neighborhood Antisense lncRNAs HNF1α-AS1 and HNF4α-AS1 2.1. Classification of lncRNAs Based on Genomic Locations 2.1. Classification of lncRNAs Based on Genomic Locations lncRNA genes can be found in several different locations relative to coding genes in the genomes lncRNA genes can be found in several different locations relative to coding genes in the genomes (Figure 1) [9]. Intergenic lncRNAs (lincRNAs) are lncRNAs located between two coding genes. (Figure1)[ 9]. Intergenic lncRNAs (lincRNAs) are lncRNAs located between two coding genes. Intronic lncRNAs are lncRNAs positioned within the intronic region of a coding gene. Sense lncRNAs Intronic lncRNAs are lncRNAs positioned within the intronic region of a coding gene. Sense lncRNAs are lncRNAs transcribed from the same strand of a coding gene, while antisense lncRNAs are are lncRNAs transcribed from the same strand of a coding gene, while antisense lncRNAs are lncRNAs lncRNAs transcribed from the opposite strand of a coding gene. transcribed from the opposite strand of a coding gene. Figure 1. Classification of lncRNAs based on genomic locations with: (A) intergenic lncRNA; (B) intronic Figure 1. Classification of lncRNAs based on genomic locations with: (A) intergenic lncRNA; (B) lncRNA; (C) sense lncRNA; and (D) antisense lncRNA. intronic lncRNA; (C) sense lncRNA; and (D) antisense lncRNA. lncRNAs can also be divided into cis-acting or trans-acting lncRNAs based on their functional type [lncRNAs10,11]. lncRNAs can also acting be divided as cis-regulators into cis-acting are mainlyor trans- involvedacting lncRNAs in the expression based on andtheir function functional of theirtype neighborhood[10,11]. lncRNAs coding acting genes, as cis- whichregulators are also are likelymainly to involved show expression in the expression correlation and with function coding of genes.their neighborhood Examples for ciscoding-acting genes, lncRNAs which include are also lncRNA likely VIM-AS1 to show andexpression CARMEN correlation [12,13]. Onwith the coding other hand,genes.trans Examples-regulatory for cis- lncRNAsacting arelncRNAs involved include in the lncRNA regulation VIM-AS1 of distal and genes CARMEN from their [12,13]. transcription On the sites,other wherehand, lncRNAtrans-regulatory FIRRE is lncRNAs an example are [14involved]. However, in the with regulation the progression of distal ingenes understanding from their lncRNAtranscription function, sites, lncRNAs where withlncRNA both cisFIRRE- and istrans an-regulatory example [14]. functions However, have beenwith identified, the progression where the in lncRNAunderstanding lncKdm2b lncRNA is an examplefunction, [15lncRNAs,16]. with both cis- and trans-regulatory functions have been identified, where the lncRNA lncKdm2b is an example [15,16]. 2.2. Neighborhood Antisense lncRNAs to Sense Genes 2.2. Neighborhood Antisense lncRNAs to Sense Genes An antisense transcript refers to a transcript generated from the opposite strand to a protein-coding or senseAn antisense strand [17 transcript]. The existence refers to ofa transcript antisense generated transcription from is the very opposite common strand across to a di protein-fferent transcriptomescoding or sense and strand these [17]. antisense The existence transcripts of areantise usuallynse transcription co-transcribed is withvery their common sense across transcripts different [18]. Ittranscriptomes has been demonstrated and these that antisense more than transcripts 60% of theare senseusually transcripts co-transcribed have antisense with their partners sense transcripts [17,19,20]. Antisense[18]. It has transcripts been demonstrated have been reported that more to havethan multiple60% of the functions sense transcripts in the regulation have ofantisense gene expression, partners which[17,19,20]. have Antisense further impacts transcripts on human have healthbeen reported and diseases to have [21 ,multiple22]. functions in the regulation of gene expression, which