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TH upstream-inhibited UBR5 subnetwork for learning in human left hemisphere|Prostate via nucleus to # 5 binding Wang Yuanzhen, WANG Lin, HUANG Juxiang** (School of Electronic Engineering, Beijing University of Posts and Telecommunications, 100876) Abstract: High tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) molecular subnetwork was constructed, including feedback sulfotransferase 10 family 1A member 2 (SULT1A2); downstream 10 open reading frame 10 (C10orf10), heterogeneous nuclear ribonucleoprotein H3 (HNRPH3), UPF3 regulator of nonsense transcripts homolog A (yeast) (UPF3A) reported relation with learning in human left hemisphere. The common biology process of TH upstream-inhibited UBR5 subnetwork was identified by DAVID, containing feedback SULT1A2, downstream HNRPH3, downstream UPF3A, second-core UBR5, first-core TH as 15 protein binding; downstream HNRPH3, downstream UPF3A, second-core UBR5 as RNA binding; feedback SULT1A2, first-core TH as small molecule metabolic process; downstream HNRPH3, downstream UPF3A as nucleotide binding; The common cellular component of downstream HNRPH3, downstream UPF3A, second-core UBR5, first-core TH as nucleus; feedback SULT1A2, downstream UPF3A, first-core TH as cytosol; downstream HNRPH3, downstream UPF3A, second-core UBR5 as 20 nucleoplasm; downstream UPF3A, second-core UBR5, first-core TH as cytoplasm; downstream C10orf10, first-core TH as mitochondrion; The common tissue distributions as Prostate_3rd maybe exist the same pattern with human left hemisphere. We propose and mutual positively verify tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork for learning in human left hemisphere|Prostate via nucleus to cytoplasm protein binding. 25 Key words: TH upstream-inhibited UBR5 subnetwork for learning; human left hemisphere|Prostate; nucleus to cytoplasm; protein binding

0 Introduction 30 Our aim is to propose and verify learning mechanism by systematic computation via tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork in human left hemisphere. TH is involved in learning and memory by Database for Annotation, Visualization and Integrated Discovery (DAVID) [1, 2]. UBR5 related molecules have been published associations with learning, memory and cognition in the references. Such as, E3 35 ubiquitin ligase RNF13 involves spatial learning and assembly of the SNARE complex[3]. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation[4]. Mutation of the HERC 1 Ubiquitin Ligase Impairs Associative Learning in the Lateral Amygdala[5]. The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning[6]. Ubiquitin ligase TRIM3 40 controls hippocampal plasticity and learning by regulating synaptic gamma-actin levels[7]. High UBR5 feedback/up/downstream direct and indirect activated molecular network will be constructed from TH upstream-inhibited database in human left hemisphere by the integration of significance analysis of microarrays (SAM), Pearson and (protein) reconstruction network inference (GRNInfer) [8]. The common biology process, cellular component and tissue distribution

Foundations: National Natural Science Youth Foundation of China (81501372) Brief author introduction: Wang Yuanzhen(1995-), Male, Master, Bioinformation Correspondance author: WANG Lin(1964-), Famale, Professor, Bioinformation. E-mail: [email protected]

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45 of TH upstream-inhibited network in chimpanzee will be setup and compared with TH upstream-inhibited UBR5 subnetwork in human left hemisphere by DAVID.

1 Results High TH upstream-inhibited UBR5 molecular subnetwork includes upstream no result, feedback SULT1A2, downstream C10orf10, HNRPH3, UPF3A in human left hemisphere from 50 our established TH inhibited database successively by SAM (fold change ≥ 2), Pearson negative correlation coefficient (CC≤-0.25) and GRNInfer from 441 significant expression molecules of 12,558 in 14 human left hemispheres compared with 15 chimpanzee, as shown in Figure 1.

Fig. 1 High TH upstream-inhibited UBR5 molecular subnetwork construction in human left hemisphere by 55 GRNInfer. Solid line with black arrow and empty circle represents UBR5 directed activated and TH directed inhibited relationship subnetwork. Dashed line with black arrow represents UBR5 indirected activated subnetwork.

High TH upstream-inhibited UBR5 molecular subnetwork contains sulfotransferase family 1A member 2, open reading frame 10, heterogeneous nuclear ribonucleoprotein 60 H3, UPF3 regulator of nonsense transcripts homolog A (yeast), ubiquitin protein ligase E3 component n-recognin 5 in human left hemisphere. The common biology process of high TH upstream-inhibited UBR5 molecular subnetwork appears protein binding, RNA binding, small molecule metabolic process, nucleotide binding in human left hemisphere. The common biology process of high TH upstream-inhibited UBR5 molecular subnetwork demonstrates nucleus, 65 cytosol, nucleoplasm, cytoplasm, mitochondrion in human left hemisphere. The common tissue

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distribution of high TH upstream-inhibited UBR5 molecular subnetwork exhibits Prostate_3rd in human left hemisphere, as shown in Table 1.

Table 1 The common biology process, cellular component and tissue distribution of TH upstream-inhibited UBR5 70 molecular subnetwork in human left hemisphere by DAVID. The common biology process, cellular component and tissue distribution of TH upstream-inhibited UBR5 molecular subnetwork in human left hemisphere Molecules Terms Num. SULT1A2, HNRPH3, UPF3A, UBR5, TH protein binding 5 HNRPH3, UPF3A, UBR5 RNA binding 3 SULT1A2, TH small molecule metabolic process 2 HNRPH3, UPF3A nucleotide binding 2 HNRPH3, UPF3A, UBR5, TH nucleus 4 SULT1A2, UPF3A, TH cytosol 3 HNRPH3, UPF3A, UBR5 nucleoplasm 3 UPF3A, UBR5, TH cytoplasm 3 C10orf10, TH mitochondrion 2 SULT1A2, C10orf10, HNRPH3, UPF3A, Prostate_3rd 6 UBR5, TH

2 Discussion High TH upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) molecular subnetwork contains feedback sulfotransferase family 1A member 2 (SULT1A2); 75 downstream chromosome 10 open reading frame 10 (C10orf10), heterogeneous nuclear ribonucleoprotein H3 (HNRPH3), UPF3 regulator of nonsense transcripts homolog A (yeast) (UPF3A) in human left hemisphere by DAVID (Table 1). High TH upstream-inhibited UBR5 molecular subnetwork of SULT1A2，C10orf10， HNRPH3，UPF3A and family members have been reported relationship with learning, memory 80 and cognition in the references. Such as, Learning disability in a son and premature ovarian failure as clinical pointers to identify a premutation on the X chromosome in a female with long-standing tremor [9]. Genetic evidence for chromosome 4 loci influencing learning and memory [10]. Children with chromosome 22q11.2 deletion syndrome exhibit impaired spatial working memory [11]. A genome wide association study of mathematical ability reveals an association at chromosome 85 3q29, a locus associated with autism and learning difficulties: a preliminary study [12]. Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice [13]. Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning [14]. The common biology process of high TH upstream-inhibited UBR5 molecular subnetwork 90 was identified feedback SULT1A2, downstream HNRPH3, downstream UPF3A, second-core UBR5, first-core TH as protein binding; downstream HNRPH3, downstream UPF3A, second-core UBR5 as RNA binding; feedback SULT1A2, first-core TH as small molecule metabolic process;

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downstream HNRPH3, downstream UPF3A as nucleotide binding in human left hemisphere (Figure 1, Table 1). We propose and mutual positively verify tyrosine hydroxylase (TH) 95 upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork for learning in human left hemisphere via protein binding. The common cellular component of high TH upstream-inhibited UBR5 molecular subnetwork was identified downstream HNRPH3, downstream UPF3A, second-core UBR5, first-core TH as nucleus; feedback SULT1A2, downstream UPF3A, first-core TH as cytosol; downstream 100 HNRPH3, downstream UPF3A, second-core UBR5 as nucleoplasm; downstream UPF3A, second-core UBR5, first-core TH as cytoplasm; downstream C10orf10, first-core TH as mitochondrion in human left hemisphere (Figure 1, Table 1). We propose and mutual positively verify tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork for learning in human left hemisphere via nucleus to cytoplasm 105 protein binding. The common tissue distribution of high TH upstream-inhibited UBR5 molecular subnetwork was identified feedback SULT1A2, downstream C10orf10, downstream HNRPH3, downstream UPF3A, second-core UBR5, first-core TH as Prostate_3rd in human left hemisphere (Figure 1, Table 1). Prostate_3rd maybe exist the same pattern with human left hemisphere. We put forward 110 and mutual positively verify tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork for learning in human left hemisphere|Prostate via nucleus to cytoplasm protein binding. The corresponding low TH upstream-inhibited network negatively verify our hypothesis in chimpanzee left hemisphere (Supplement 5-6).

115 3 Methods 441 high expression significant molecular database was identified from 12,558 genes in 14 human left hemispheres compared with 15 chimpanzee in GDS2678 [15] for studying tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork, including the brain cerebrum, anterior cingulate cortex, anterior inferior parietal 120 cortex, anterior inferior temporal cortex, middle frontal gyrus, the frontal pole, etc. by SAM [16] (http://www-stat.stanford.edu/~tibs/SAM/). Data were processed using a log base of two and two unpaired classes with minimum fold change (≥ 2). A false-discovery rate of 0% was chosen. We declare the study data GDS2678 public free from NCBI. Pearson negative correlation coefficient (CC≤-0.25) database with TH in human left 125 hemisphere was calculated from our established total 441 high expression significant molecular database by SPSS. The other mutual positive Pearson correlation (CC≥0.25) molecules except TH were computed in human left hemisphere based on the above molecular database. High TH upstream-inhibited molecular network was constructed based on the above TH inhibited mutual positive Pearson correlation database in human left hemisphere by GRNInfer [8, 130 17-23]. High UBR5 feedback/up/downstream direct and indirect activated molecular subnetwork

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was constructed from our established TH upstream-inhibited molecular database in human left hemisphere. GRNInfer is a tool used to infer high TH upstream-inhibited network based on linear programming and the decomposition procedure defined by the following equation:

135 The common biology processes, cellular components and tissue distribution of low TH upstream-inhibited network in chimpanzee were setup and compared with high TH upstream-inhibited UBR5 subnetwork in human left hemisphere based on our TH upstream-inhibited GOTERM_MF_DIRECT, GOTERM_BP_DIRECT, GOTERM_CC_DIRECT, GNF_U133A_QUARTILE and UNIGENE_EST_QUARTILE database by DAVID [1, 2] 140 (https://david.ncifcrf.gov/), respectively.

4 Conclusion We put forward and verify tyrosine hydroxylase (TH) upstream-inhibited ubiquitin protein ligase E3 component n-recognin 5 (UBR5) subnetwork for learning in human left hemisphere|Prostate via nucleus to cytoplasm protein binding. Other TH inhibited subnetworks 145 will be computed and analyzed for the molecular and cellular mechanisms of learning in the future. Our findings provide a new avenue to understand the molecular and cellular mechanisms of learning.

References

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220 人左脑|前列腺中TH上游抑制UBR5学习子 网通过细胞核到质的蛋白结合 王元臻，王琳，黄菊香 （北京邮电大学电子工程学院，100876） 摘要：本文通过GRNInfer构建了人类左脑中酪氨酸羟化酶（TH）上游抑制泛素蛋白连接酶 225 E3组分n-识别蛋白5（UBR5）的分子亚网包括反馈磺基转移酶家族1A成员2（SULT1A2）; 下 游10号染色体开放阅读框10（C10orf10），异质核糖核蛋白H3（HNRPH3），UPF3调节子 的无义转录同源物A（酵母）（UPF3A），这些分子均与学习有关。基于DAVID，确定了 TH上游抑制UBR5亚网相同的生物过程，包括反馈SULT1A2，下游HNRPH3，下游UPF3A， 次中心UBR5，主中心TH的蛋白结合; 下游HNRPH3，下游UPF3A，次中心UBR5的RNA结 230 合; 反馈SULT1A2，主中心TH的小分子代谢过程； 下游HNRPH3，下游UPF3A的核苷酸结 合。相应的相同的细胞定位包含下游HNRPH3，下游UPF3A，次中心UBR5，主中心TH的核; 反馈SULT1A2，下游UPF3A，主中心TH的胞质溶胶； 下游HNRPH3，下游UPF3A，次中心 UBR5的核质； 下游UPF3A，次中心UBR5，主中心TH的细胞质； 下游C10orf10，主中心 TH的线粒体。相应的相同的组织分布有前列腺_3rd可能与人类左脑存在相同的模式。我们 235 提出并相互验证酪氨酸羟化酶（TH）上游抑制泛素蛋白连接酶E3组分n-识别蛋白5（UBR5） 子网在人左脑|前列腺中的学习通过细胞核到质的蛋白结合。 关键词：TH上游抑制UBR5学习子网; 人左脑|前列腺; 细胞核到质; 蛋白结合 中图分类号：Q291

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